Metalloenzyme inhibitor compounds as fungicides

ABSTRACT

The instant invention describes compounds of Formula I having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 14/683,907 filed Apr. 10, 2015, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/979,543 filed Apr. 15, 2014 and U.S. Provisional Patent Application Ser. No. 62/047,368 filed Sep. 8, 2014, each of which is expressly incorporated by reference herein in its entirety as if each were incorporated by reference herein individually.

BACKGROUND & SUMMARY

Fungicides are compounds, of natural or synthetic origin, which act to protect and/or cure plants against damage caused by agriculturally relevant fungi. Generally, no single fungicide is useful in all situations. Consequently, research is ongoing to produce fungicides that may have better performance, are easier to use, and cost less.

The present disclosure relates to metalloenzyme inhibitors and their use as fungicides. The compounds of the present disclosure may offer protection against ascomycetes, basidiomycetes, deuteromycetes and oomycetes.

One embodiment of the present disclosure may include compounds of Formula I:

Where:

Z is optionally substituted 5-pyrimidinyl, optionally substituted 4-pyrimidinyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted 3-pyridinyl, or optionally substituted 4-pyridinyl;

n is 0 or 1;

R₁ is alkyl, haloalkyl, aryl, or heteroaryl, each optionally substituted with 0, 1, 2 or 3 independent R₄;

R₂ is aryl, heteroaryl aryloxy, heteroaryloxy, arylalkynyl, heteroarylalkynyl, arylalkyl, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, aryloxyalkyl, or heteroaryloxyalkyl wherein each aryl or heteroaryl is optionally substituted with 0, 1, 2 or 3 independent R₄;

R₃ is independently H, alkyl, aryl, substituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl, —C(O)alkyl, —C(O)aryl, —Si(alkyl)₃, each optionally substituted with 0, 1, 2 or 3 independent R₄;

R₄ is independently aryl, heteroaryl, alkyl, thioalkyl, cyano, cyanoalkyl, haloalkyl, hydroxy, alkoxy, halo, haloalkoxy, —C(O)alkyl, —C(O)OH, —C(O)Oalkyl, —SCF₃, —SF₅, —SCN, or SO₂(alkyl); and

R₅-R₇ are independently selected from the group consisting of H, alkyl, alkoxy, halo, and haloalkyl;

With the proviso that when n=1, Z is 1-tetrazolyl or 5-pyrimidinyl.

Another embodiment of the present disclosure may include a fungicidal composition for the control or prevention of fungal attack comprising the compounds described above and a phytologically acceptable carrier material.

Yet another embodiment of the present disclosure may include a method for the control or prevention of fungal attack on a plant, the method including the steps of applying a fungicidally effective amount of one or more of the compounds described above to at least one of the fungus, the plant, and an area adjacent to the plant.

It will be understood by those skilled in the art that the following terms may include generic “R”-groups within their definitions, e.g., “the term alkoxy refers to an —OR substituent”. It is also understood that within the definitions for the following terms, these “R” groups are included for illustration purposes and should not be construed as limiting or being limited by substitutions about Formula I.

The term “alkyl” refers to a branched, unbranched, or saturated cyclic carbon chain, including, but not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term “alkenyl” refers to a branched, unbranched or cyclic carbon chain containing one or more double bonds including, but not limited to, ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

The term “alkynyl” refers to a branched or unbranched carbon chain containing one or more triple bonds including, but not limited to, propynyl, butynyl and the like.

The term “aryl” or “Ar” refers to any aromatic ring, mono- or bi-cyclic, containing 0 heteroatoms.

The term “heterocycle” refers to any aromatic or non-aromatic ring, mono- or bi-cyclic, containing one or more heteroatoms.

The term “heteroaryl” or “Het” refers to any aromatic ring, mono- or bi-cyclic, containing one or more heteroatoms.

The term “alkoxy” refers to an —OR substituent.

The term “aryloxy” refers to an —OAr substituent.

The term “hetaryloxy” refers to an —OHet substituent.

The term “arylalkynyl” refers to an —≡—Ar substituent.

The term “heteroarylalkynyl” refers to an -≡-Het substituent.

The term “cyano” refers to a —C≡N substituent.

The term “hydroxyl” refers to an —OH substituent.

The term “amino” refers to a —NR₂ substituent.

The term “arylalkyl” refers to an -alkyl-Ar substituent.

The term “heteroarylalkyl” refers to an -alkyl-Het substituent.

The term “arylalkoxy” refers to —O(CH₂)_(n)Ar where n is an integer selected from the list 1, 2, 3, 4, 5, or 6.

The term “heteroarylalkoxy” refers to —O(CH₂)_(n)Het where n is an integer selected from the list 1, 2, 3, 4, 5, or 6.

The term “haloalkoxy” refers to an —OR substituent, wherein R is substituted with Cl, F, Br, or I, or any combination of one or more halogen atoms.

The term “haloalkyl” refers to an alkyl, which is substituted with one or more halogen atoms.

The term “cyanoalkyl” refers to an alkyl, which is substituted with a cyano group.

The term “halogen” or “halo” refers to one or more halogen atoms, defined as F, Cl, Br, and I.

The term “nitro” refers to a —NO₂ substituent.

The term thioalkyl refers to an —SR substituent.

Throughout the disclosure, reference to the compounds of Formula I is read as also including diastereomers, enantiomers, and mixtures thereof. In another embodiment, Formula I is read as also including salts or hydrates thereof. Exemplary salts include, but are not limited to: hydrochloride, hydrobromide, and hydroiodide.

It is also understood by those skilled in the art that additional substitution is allowable, unless otherwise noted, as long as the rules of chemical bonding and strain energy are satisfied and the product still exhibits fungicidal activity.

Another embodiment of the present disclosure is a use of a compound of Formula I, for protection of a plant against attack by a phytopathogenic organism or the treatment of a plant infested by a phytopathogenic organism, comprising the application of a compound of Formula I, or a composition comprising the compound to soil, a plant, a part of a plant, foliage, seeds, and/or roots.

Additionally, another embodiment of the present disclosure is a composition useful for protecting a plant against attack by a phytopathogenic organism and/or treatment of a plant infested by a phytopathogenic organism comprising a compound of Formula I and a phytologically acceptable carrier material.

DETAILED DESCRIPTION

The compounds of the present disclosure may be applied by any of a variety of known techniques, either as the compounds or as formulations comprising the compounds. For example, the compounds may be applied to the seeds, roots or foliage of plants for the control of various fungi, without damaging the commercial value of the plants. The materials may be applied in the form of any of the generally used formulation types, for example, as solutions, dusts, wettable powders, flowable concentrate, or emulsifiable concentrates.

Preferably, the compounds of the present disclosure are applied in the form of a formulation, comprising one or more of the compounds of Formula I with a phytologically acceptable carrier. Concentrated formulations may be dispersed in water, or other liquids, for application, or formulations may be dust-like or granular, which may then be applied without further treatment. The formulations may be prepared according to procedures that are conventional in the agricultural chemical art.

The present disclosure contemplates all vehicles by which one or more of the compounds may be formulated for delivery and use as a fungicide. Typically, formulations are applied as aqueous suspensions or emulsions. Such suspensions or emulsions may be produced from water-soluble, water-suspendible, or emulsifiable formulations which are solids, usually known as wettable powders; or liquids, usually known as emulsifiable concentrates, aqueous suspensions, or suspension concentrates. As will be readily appreciated, any material to which these compounds may be added may be used, provided it yields the desired utility without significant interference with the activity of these compounds as antifungal agents.

Wettable powders, which may be compacted to form water-dispersible granules, comprise an intimate mixture of one or more of the compounds of Formula I, an inert carrier and surfactants. The concentration of the compound in the wettable powder may be from about 10 percent to about 90 percent by weight based on the total weight of the wettable powder, more preferably about 25 weight percent to about 75 weight percent. In the preparation of wettable powder formulations, the compounds may be compounded with any finely divided solid, such as prophyllite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite clays, diatomaceous earths, purified silicates or the like. In such operations, the finely divided carrier and surfactants are typically blended with the compound(s) and milled.

Emulsifiable concentrates of the compounds of Formula I may comprise a convenient concentration, such as from about 1 weight percent to about 50 weight percent of the compound, in a suitable liquid, based on the total weight of the concentrate. The compounds may be dissolved in an inert carrier, which is either a water-miscible solvent or a mixture of water-immiscible organic solvents, and emulsifiers. The concentrates may be diluted with water and oil to form spray mixtures in the form of oil-in-water emulsions. Useful organic solvents include aromatics, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, for example, terpenic solvents, including rosin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols, such as 2-ethoxyethanol.

Emulsifiers which may be advantageously employed herein may be readily determined by those skilled in the art and include various nonionic, anionic, cationic and amphoteric emulsifiers, or a blend of two or more emulsifiers. Examples of nonionic emulsifiers useful in preparing the emulsifiable concentrates include the polyalkylene glycol ethers and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxides such as the ethoxylated alkyl phenols and carboxylic esters solubilized with the polyol or polyoxyalkylene. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emulsifiers include the oil-soluble salts (e.g., calcium) of alkylaryl sulphonic acids, oil-soluble salts or sulfated polyglycol ethers and appropriate salts of phosphated polyglycol ether.

Representative organic liquids which may be employed in preparing the emulsifiable concentrates of the compounds of the present disclosure are the aromatic liquids such as xylene, propyl benzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkyl amides of various fatty acids, particularly the dimethyl amides of fatty glycols and glycol derivatives such as the n-butyl ether, ethyl ether or methyl ether of diethylene glycol, the methyl ether of triethylene glycol, petroleum fractions or hydrocarbons such as mineral oil, aromatic solvents, paraffinic oils, and the like; vegetable oils such as soy bean oil, rape seed oil, olive oil, castor oil, sunflower seed oil, coconut oil, corn oil, cotton seed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, tung oil and the like; esters of the above vegetable oils; and the like. Mixtures of two or more organic liquids may also be employed in the preparation of the emulsifiable concentrate. Organic liquids include xylene, and propyl benzene fractions, with xylene being most preferred in some cases. Surface-active dispersing agents are typically employed in liquid formulations and in an amount of from 0.1 to 20 percent by weight based on the combined weight of the dispersing agent with one or more of the compounds. The formulations may also contain other compatible additives, for example, plant growth regulators and other biologically active compounds used in agriculture.

Aqueous suspensions comprise suspensions of one or more water-insoluble compounds of Formula I, dispersed in an aqueous vehicle at a concentration in the range from about 1 to about 50 weight percent, based on the total weight of the aqueous suspension. Suspensions are prepared by finely grinding one or more of the compounds, and vigorously mixing the ground material into a vehicle comprised of water and surfactants chosen from the same types discussed above. Other components, such as inorganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous vehicle.

The compounds of Formula I may also be applied as granular formulations, which are particularly useful for applications to the soil. Granular formulations generally contain from about 0.5 to about 10 weight percent, based on the total weight of the granular formulation of the compound(s), dispersed in an inert carrier which consists entirely or in large part of coarsely divided inert material such as attapulgite, bentonite, diatomite, clay or a similar inexpensive substance. Such formulations are usually prepared by dissolving the compounds in a suitable solvent and applying it to a granular carrier which has been preformed to the appropriate particle size, in the range of from about 0.5 to about 3 mm. A suitable solvent is a solvent in which the compound is substantially or completely soluble. Such formulations may also be prepared by making a dough or paste of the carrier and the compound and solvent, and crushing and drying to obtain the desired granular particle.

Dusts containing the compounds of Formula I may be prepared by intimately mixing one or more of the compounds in powdered form with a suitable dusty agricultural carrier, such as, for example, kaolin clay, ground volcanic rock, and the like. Dusts may suitably contain from about 1 to about 10 weight percent of the compounds, based on the total weight of the dust.

The formulations may additionally contain adjuvant surfactants to enhance deposition, wetting and penetration of the compounds onto the target crop and organism. These adjuvant surfactants may optionally be employed as a component of the formulation or as a tank mix. The amount of adjuvant surfactant will typically vary from 0.01 to 1.0 percent by volume, based on a spray-volume of water, preferably 0.05 to 0.5 volume percent. Suitable adjuvant surfactants include, but are not limited to ethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols, salts of the esters or sulphosuccinic acids, ethoxylated organosilicones, ethoxylated fatty amines, blends of surfactants with mineral or vegetable oils, crop oil concentrate (mineral oil (85%)+emulsifiers (15%)); nonylphenol ethoxylate; benzylcocoalkyldimethyl quaternary ammonium salt; blend of petroleum hydrocarbon, alkyl esters, organic acid, and anionic surfactant; C₉-C₁₁ alkylpolyglycoside; phosphated alcohol ethoxylate; natural primary alcohol (C₁₂-C₁₆) ethoxylate; di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl cap; nonylphenol ethoxylate+urea ammonium nitrrate; emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate (8EO); tallow amine ethoxylate (15 EO); PEG(400) dioleate-99. The formulations may also include oil-in-water emulsions such as those disclosed in U.S. patent application Ser. No. 11/495,228, the disclosure of which is expressly incorporated by reference herein.

The formulations may optionally include combinations that contain other pesticidal compounds. Such additional pesticidal compounds may be fungicides, insecticides, herbicides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the compounds of the present disclosure in the medium selected for application, and not antagonistic to the activity of the present compounds. Accordingly, in such embodiments, the other pesticidal compound is employed as a supplemental toxicant for the same or for a different pesticidal use. The compounds of Formula I and the pesticidal compound in the combination may generally be present in a weight ratio of from 1:100 to 100:1.

The compounds of the present disclosure may also be combined with other fungicides to form fungicidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure are often applied in conjunction with one or more other fungicides to control a wider variety of undesirable diseases. When used in conjunction with other fungicide(s), the presently claimed compounds may be formulated with the other fungicide(s), tank-mixed with the other fungicide(s) or applied sequentially with the other fungicide(s). Such other fungicides may include 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin, Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus subtilis, Bacillus subtilis strain QST713, benalaxyl, benomyl, benthiavalicarb-isopropyl, benzovindiflupyr, benzylaminobenzene-sulfonate (BABS) salt, bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole, bupirimate, calcium polysulfide, captafol, captan, carbendazim, carboxin, carpropamid, carvone, chlazafenone, chloroneb, chlorothalonil, chlozolinate, Coniothyrium minitans, copper hydroxide, copper octanoate, copper oxychloride, copper sulfate, copper sulfate (tribasic), cuprous oxide, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, dazomet, debacarb, diammonium ethylenebis-(dithiocarbamate), dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran, diethofencarb, difenoconazole, difenzoquat ion, diflumetorim, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton, dinocap, diphenylamine, dithianon, dodemorph, dodemorph acetate, dodine, dodine free base, edifenphos, enestrobin, enestroburin, epoxiconazole, ethaboxam, ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fenpyrazamine, fentin, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumorph, fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutianil, flutolanil, flutriafol, fluxapyroxad, folpet, formaldehyde, fosetyl, fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetates, GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalil sulfate, imibenconazole, iminoctadine, iminoctadine triacetate, iminoctadine tris(albesilate), iodocarb, ipconazole, ipfenpyrazolone, iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam, isotianil, kasugamycin, kasugamycin hydrochloride hydrate, kresoxim-methyl, laminarin, mancopper, mancozeb, mandipropamid, maneb, mefenoxam, mepanipyrim, mepronil, meptyl-dinocap, mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl, metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium, metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate, metiram, metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam, nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fatty acids), orysastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen, pentachlorophenol, pentachlorophenyl laurate, penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide, picoxystrobin, polyoxin B, polyoxins, polyoxorim, potassium bicarbonate, potassium hydroxyquinoline sulfate, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, proquinazid, prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyriofenone, pyroquilon, quinoclamine, quinoxyfen, quintozene, Reynoutria sachalinensis extract, sedaxane, silthiofam, simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodium pentachlorophenoxide, spiroxamine, sulfur, SYP-Z048, tar oils, tebuconazole, tebufloquin, tecnazene, tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole, validamycin, valifenalate, valiphenal, vinclozolin, zineb, ziram, zoxamide, Candida oleophila, Fusarium oxysporum, Gliocladium spp., Phlebiopsis gigantea, Streptomyces griseoviridis, Trichoderma spp., (RS)—N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide, 1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane, 2-(2-heptadecyl-2-imidazolin-1-yl)ethanol, 2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide, 2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride, 2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5-methylrhodanine, 4-(2-nitroprop-1-enyl)phenyl thiocyanateme, ampropylfos, anilazine, azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox, bentaluron, benzamacril; benzamacril-isobutyl, benzamorf, binapacryl, bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmium calcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone, chloraniformethan, chlorfenazole, chlorquinox, climbazole, copper bis(3-phenylsalicylate), copper zinc chromate, cufraneb, cupric hydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, cyprofuram, decafentin, dichlone, dichlozoline, diclobutrazol, dimethirimol, dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin, drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf, fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole, furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin, halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos, isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam, methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride, myclozolin, N-3,5-dichlorophenyl-succinimide, N-3-nitrophenylitaconimide, natamycin, N-ethylmercurio-4-toluenesulfonanilide, nickel bis(dimethyldithiocarbamate), OCH, phenylmercury dimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb; prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quinazamid, quinconazole, rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor, thicyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid, triamiphos, triarimol, triazbutil, trichlamide, urbacid, zarilamid, and any combinations thereof.

Additionally, the compounds described herein may be combined with other pesticides, including insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the compounds of the present disclosure in the medium selected for application, and not antagonistic to the activity of the present compounds to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure may be applied in conjunction with one or more other pesticides to control a wider variety of undesirable pests. When used in conjunction with other pesticides, the presently claimed compounds may be formulated with the other pesticide(s), tank-mixed with the other pesticide(s) or applied sequentially with the other pesticide(s). Typical insecticides include, but are not limited to: 1,2-dichloropropane, abamectin, acephate, acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile, alanycarb, aldicarb, aldoxycarb, aldrin, allethrin, allosamidin, allyxycarb, alpha-cypermethrin, alpha-ecdysone, alpha-endosulfan, amidithion, aminocarb, amiton, amiton oxalate, amitraz, anabasine, athidathion, azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin, bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin, bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bistrifluron, borax, boric acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos, bromophos-ethyl, bufencarb, buprofezin, butacarb, butathiofos, butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate, calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, cartap, cartap hydrochloride, chlorantraniliprole, chlorbicyclen, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos, chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chromafenozide, cinerin I, cinerin II, cinerins, cismethrin, cloethocarb, closantel, clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate, copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos, crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos, diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos, dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor, dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos, dimetilan, dinex, dinex-diclexine, dinoprop, dinosam, dinotefuran, diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton, dithicrofos, d-limonene, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, doramectin, ecdysterone, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothion, endrin, EPN, epofenonane, eprinomectin, esdepalléthrine, esfenvalerate, etaphos, ethiofencarb, ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl formate, ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide, etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor, fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb, fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion, fenthion, fenthion-ethyl, fenvalerate, fipronil, flonicamid, flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim, flufenoxuron, flufenprox, fluvalinate, fonofos, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosmethilan, fospirate, fosthietan, furathiocarb, furethrin, gamma-cyhalothrin, gamma-HCH, halfenprox, halofenozide, HCH, HEOD, heptachlor, heptenophos, heterophos, hexaflumuron, HHDN, hydramethylnon, hydrogen cyanide, hydroprene, hyquincarb, imidacloprid, imiprothrin, indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos, isodrin, isofenphos, isofenphos-methyl, isoprocarb, isoprothiolane, isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kelevan, kinoprene, lambda-cyhalothrin, lead arsenate, lepimectin, leptophos, lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben, mazidox, mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride, mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion, methiocarb, methocrotophos, methomyl, methoprene, methoxychlor, methoxyfenozide, methyl bromide, methyl isothiocyanate, methylchloroform, methylene chloride, metofluthrin, metolcarb, metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime, mipafox, mirex, molosultap, monocrotophos, monomehypo, monosultap, morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine, nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron, noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos, oxydisulfoton, para-dichlorobenzene, parathion, parathion-methyl, penfluron, pentachlorophenol, permethrin, phenkapton, phenothrin, phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor, phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite, potassium thiocyanate, pp′-DDT, prallethrin, precocene I, precocene II, precocene III, primidophos, profenofos, profluralin, promacyl, promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos, prothoate, protrifenbute, pyraclofos, pyrafluprole, pyrazophos, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyridaben, pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate, pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl, quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadilla, schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodium fluoride, sodium hexafluorosilicate, sodium thiocyanate, sophamide, spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron, sulcofuron-sodium, sulfluramid, sulfotep, sulfoxaflor, sulfuryl fluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenozide, tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, TEPP, terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos, tetramethrin, tetramethylfluthrin, theta-cypermethrin, thiacloprid, thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiocyclam oxalate, thiodicarb, thiofanox, thiometon, thiosultap, thiosultap-disodium, thiosultap-monosodium, thuringiensin, tolfenpyrad, tralomethrin, transfluthrin, transpermethrin, triarathene, triazamate, triazophos, trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumuron, trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb, zeta-cypermethrin, zolaprofos, and any combinations thereof.

Additionally, the compounds described herein may be combined with herbicides that are compatible with the compounds of the present disclosure in the medium selected for application, and not antagonistic to the activity of the present compounds to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure may be applied in conjunction with one or more herbicides to control a wide variety of undesirable plants. When used in conjunction with herbicides, the presently claimed compounds may be formulated with the herbicide(s), tank-mixed with the herbicide(s) or applied sequentially with the herbicide(s). Typical herbicides include, but are not limited to: 4-CPA; 4-CPB; 4-CPP; 2,4-D; 3,4-DA; 2,4-DB; 3,4-DB; 2,4-DEB; 2,4-DEP; 3,4-DP; 2,3,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor, acifluorfen, aclonifen, acrolein, alachlor, allidochlor, alloxydim, allyl alcohol, alorac, ametridione, ametryn, amibuzin, amicarbazone, amidosulfuron, aminocyclopyrachlor, aminopyralid, amiprofos-methyl, amitrole, ammonium sulfamate, anilofos, anisuron, asulam, atraton, atrazine, azafenidin, azimsulfuron, aziprotryne, barban, BCPC, beflubutamid, benazolin, bencarbazone, benfluralin, benfuresate, bensulfuron, bensulide, bentazone, benzadox, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzoylprop, benzthiazuron, bicyclopyrone, bifenox, bilanafos, bispyribac, borax, bromacil, bromobonil, bromobutide, bromofenoxim, bromoxynil, brompyrazon, butachlor, butafenacil, butamifos, butenachlor, buthidazole, buthiuron, butralin, butroxydim, buturon, butylate, cacodylic acid, cafenstrole, calcium chlorate, calcium cyanamide, cambendichlor, carbasulam, carbetamide, carboxazole chlorprocarb, carfentrazone, CDEA, CEPC, chlomethoxyfen, chloramben, chloranocryl, chlorazifop, chlorazine, chlorbromuron, chlorbufam, chloreturon, chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol, chloridazon, chlorimuron, chlomitrofen, chloropon, chlorotoluron, chloroxuron, chloroxynil, chlorpropham, chlorsulfuron, chlorthal, chlorthiamid, cinidon-ethyl, cinmethylin, cinosulfuron, cisanilide, clethodim, cliodinate, clodinafop, clofop, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, cloransulam, CMA, copper sulfate, CPMF, CPPC, credazine, cresol, cumyluron, cyanatryn, cyanazine, cycloate, cyclosulfamuron, cycloxydim, cycluron, cyhalofop, cyperquat, cyprazine, cyprazole, cypromid, daimuron, dalapon, dazomet, delachlor, desmedipham, desmetryn, di-allate, dicamba, dichlobenil, dichloralurea, dichlormate, dichlorprop, dichlorprop-P, diclofop, diclosulam, diethamquat, diethatyl, difenopenten, difenoxuron, difenzoquat, diflufenican, diflufenzopyr, dimefuron, dimepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimexano, dimidazon, dinitramine, dinofenate, dinoprop, dinosam, dinoseb, dinoterb, diphenamid, dipropetryn, diquat, disul, dithiopyr, diuron, DMPA, DNOC, DSMA, EBEP, eglinazine, endothal, epronaz, EPTC, erbon, esprocarb, ethalfluralin, ethametsulfuron, ethidimuron, ethiolate, ethofumesate, ethoxyfen, ethoxysulfuron, etinofen, etnipromid, etobenzanid, EXD, fenasulam, fenoprop, fenoxaprop, fenoxaprop-P, fenoxasulfone, fenteracol, fenthiaprop, fentrazamide, fenuron, ferrous sulfate, flamprop, flamprop-M, flazasulfuron, florasulam, fluazifop, fluazifop-P, fluazolate, flucarbazone, flucetosulfuron, fluchloralin, flufenacet, flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac, flumioxazin, flumipropyn, fluometuron, fluorodifen, fluoroglycofen, fluoromidine, fluoronitrofen, fluothiuron, flupoxam, flupropacil, flupropanate, flupyrsulfuron, fluridone, flurochloridone, fluroxypyr, flurtamone, fluthiacet, fomesafen, foramsulfuron, fosamine, furyloxyfen, glufosinate, glufosinate-P, glyphosate, halauxifen, halosafen, halosulfuron, haloxydine, haloxyfop, haloxyfop-P, hexachloroacetone, hexaflurate, hexazinone, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, imazosulfuron, indanofan, indaziflam, iodobonil, iodomethane, iodosulfuron, ioxynil, ipazine, ipfencarbazone, iprymidam, isocarbamid, isocil, isomethiozin, isonoruron, isopolinate, isopropalin, isoproturon, isouron, isoxaben, isoxachlortole, isoxaflutole, isoxapyrifop, karbutilate, ketospiradox, lactofen, lenacil, linuron, MAA, MAMA, MCPA, MCPA-thioethyl, MCPB, mecoprop, mecoprop-P, medinoterb, mefenacet, mefluidide, mesoprazine, mesosulfuron, mesotrione, metam, metamifop, metamitron, metazachlor, metazosulfuron, metflurazon, methabenzthiazuron, methalpropalin, methazole, methiobencarb, methiozolin, methiuron, methometon, methoprotryne, methyl bromide, methyl isothiocyanate, methyldymron, metobenzuron, metobromuron, metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, molinate, monalide, monisouron, monochloroacetic acid, monolinuron, monuron, morfamquat, MSMA, naproanilide, napropamide, naptalam, neburon, nicosulfuron, nipyraclofen, nitralin, nitrofen, nitrofluorfen, norflurazon, noruron, OCH, orbencarb, ortho-dichlorobenzene, orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxapyrazon, oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquat, pebulate, pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol, pentanochlor, pentoxazone, perfluidone, pethoxamid, phenisopham, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury acetate, picloram, picolinafen, pinoxaden, piperophos, potassium arsenite, potassium azide, potassium cyanate, pretilachlor, primisulfuron, procyazine, prodiamine, profluazol, profluralin, profoxydim, proglinazine, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propisochlor, propoxycarbazone, propyrisulfuron, propyzamide, prosulfalin, prosulfocarb, prosulfuron, proxan, prynachlor, pydanon, pyraclonil, pyraflufen, pyrasulfotole, pyrazolynate, pyrazosulfuron, pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclor, pyridafol, pyridate, pyriftalid, pyriminobac, pyrimisulfan, pyrithiobac, pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine, quinonamid, quizalofop, quizalofop-P, rhodethanil, rimsulfuron, saflufenacil, S-metolachlor, sebuthylazine, secbumeton, sethoxydim, siduron, simazine, simeton, simetryn, SMA, sodium arsenite, sodium azide, sodium chlorate, sulcotrione, sulfallate, sulfentrazone, sulfometuron, sulfosulfuron, sulfuric acid, sulglycapin, swep, TCA, tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine, terbutryn, tetrafluron, thenylchlor, thiazafluron, thiazopyr, thidiazimin, thidiazuron, thiencarbazone-methyl, thifensulfuron, thiobencarb, tiocarbazil, tioclorim, topramezone, tralkoxydim, triafamone, tri-allate, triasulfuron, triaziflam, tribenuron, tricamba, triclopyr, tridiphane, trietazine, trifloxysulfuron, trifluralin, triflusulfuron, trifop, trifopsime, trihydroxytriazine, trimeturon, tripropindan, tritac, tritosulfuron, vernolate, and xylachlor.

Another embodiment of the present disclosure is a method for the control or prevention of fungal attack. This method comprises applying to the soil, plant, roots, foliage, seeds, or locus of the fungus, or to a locus in which the infestation is to be prevented (for example applying to cereal or grape plants), a fungicidally effective amount of one or more of the compounds of Formula I. The compounds are suitable for treatment of various plants at fungicidal levels, while exhibiting low phytotoxicity. The compounds may be useful both in a protectant and/or an eradicant fashion.

The compounds have been found to have significant fungicidal effect particularly for agricultural use. Many of the compounds are particularly effective for use with agricultural crops and horticultural plants.

It will be understood by those in the art that the efficacy of the compound for the foregoing fungi establishes the general utility of the compounds as fungicides.

The compounds have broad ranges of activity against fungal pathogens. Exemplary pathogens may include, but are not limited to, causing agent of wheat leaf blotch (Mycosphaerella graminicola; impect stage: Septoria tritici), wheat brown rust (Puccinia triticina), wheat stripe rust (Puccinia striiformis), scab of apple (Venturia inaequalis), powdery mildew of grapevine (Uncinula necator), barley scald (Rhynchosporium secalis), blast of rice (Magnaporthe grisea), rust of soybean (Phakopsora pachyrhizi), glume blotch of wheat (Leptosphaeria nodorum), powdery mildew of wheat (Blumeria graminis f. sp. tritici), powdery mildew of barley (Blumeria graminis f. sp. hordei), powdery mildew of cucurbits (Erysiphe cichoracearum), anthracnose of cucurbits (Glomerella lagenarium), leaf spot of beet (Cercospora beticola), early blight of tomato (Alternaria solani), and spot blotch of barley (Cochliobolus sativus). The exact amount of the active material to be applied is dependent not only on the specific active material being applied, but also on the particular action desired, the fungal species to be controlled, and the stage of growth thereof, as well as the part of the plant or other product to be contacted with the compound. Thus, all the compounds, and formulations containing the same, may not be equally effective at similar concentrations or against the same fungal species.

The compounds are effective in use with plants in a disease-inhibiting and phytologically acceptable amount. The term “disease-inhibiting and phytologically acceptable amount” refers to an amount of a compound that kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant. This amount will generally be from about 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm being preferred. The exact concentration of compound required varies with the fungal disease to be controlled, the type of formulation employed, the method of application, the particular plant species, climate conditions, and the like. A suitable application rate is typically in the range from about 0.10 to about 4 pounds/acre (about 0.01 to 0.45 grams per square meter, g/m²).

Any range or desired value given herein may be extended or altered without losing the effects sought, as is apparent to the skilled person for an understanding of the teachings herein.

The compounds of Formula I may be made using well-known chemical procedures. Intermediates not specifically mentioned in this disclosure are either commercially available, may be made by routes disclosed in the chemical literature, or may be readily synthesized from commercial starting materials utilizing standard procedures.

General Schemes

The following schemes illustrate approaches to generating metalloenzyme inhibitor compounds of Formula (I). The following descriptions and examples are provided for illustrative purposes and should not be construed as limiting in terms of substituents or substitution patterns. It will be evident to one skilled in the art that many of the compounds of Formula I may be synthesized using more than one of the routes disclosed within the following schemes.

The compound of Formula 1.7, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared according to the methods outlined in Scheme 1, steps c-e from the appropriately substituted precursors, such as compounds of Formulae 1.3 and 1.4, which may be prepared according to the methods outlined in Scheme 1, steps a-b. The compound of Formula 1.3 may be prepared via the condensation of the compound of Formula 1.0 with ethyl 2,2-difluoro-2-bromoacetate activated with copper (Cu(0)) in a polar, aprotic solvent such as dimethyl sulfoxide (DMSO), as shown in step a. Compound 1.4 may be prepared by treating the suitably electron deficient 4-fluorobenzonitrile of Formula 1.1 with a nucleophile, such as the phenoxide anion of the compound of Formula 1.2, generated by treating the phenol of Formula 1.2 with an alkali carbonate base, such as cesium carbonate (Cs₂CO₃), in a polar solvent like N,N-dimethylformamide (DMF) at an elevated temperature, for example 80-100° C., as shown in step b. The ketone of Formula 1.5 may be prepared via the condensation of the compound of Formula 1.3 with an appropriately substituted nucleophile, such as the the lithiated pyridine, generated by treating the bromopyridine of Formula 1.4 with n-butyllithium (n-BuLi) in an aprotic solvent, such as toluene, at a reduced temperature of about −78° C., as shown in step c. The epoxide of Formula 1.6 may be prepared by treating the ketone of Formula 1.5 with dimethyloxosulfonium methylide, generated by treating trimethylsulfoxonium iodide with a strong base, such as potassium tert-butoxide (KO^(t)Bu) or sodium hydride (NaH) in a mixture of polar, aprotic solvents, for example tetrahydrofuran (THF) and DMSO at a reduced temperature, for example between about −20° C. and 0° C., as shown in step d. The compound of Formula 1.7, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared by treating an appropriately substituted epoxide, for example the epoxide of Formula 1.6, with a nucleophile, for example 1H-tetrazole, in the presence of an alkali carbonate base, such as potassium carbonate (K₂CO₃) in a polar solvent like DMF at an elevated temperature of about 60° C., as shown in step e.

The compound of Formula 2.5, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared according to the methods outlined in Scheme 2, steps b-d from the appropriately substituted precursors, such as compounds of Formulae 2.1 and 2.2, which may be prepared according to the methods outlined in Scheme 2, step a. The Weinreb amide of Formula 2.1 may be prepared from the propanaoic acid of Formula 2.0 using methodology reported by Trost et. al. (J. Am. Chem. Soc. 2010, 132, 8915-8917), as shown in step a. The ketone of Formula 2.3 may be prepared via the condensation of the Weinreb amide of Formula 2.1 with a nucleophile, such as a lithiated pyridine, generated via the treatment of an appropriately substituted bromopyridine, for example the bromopyridine of Formula 2.2, with n-BuLi in an aprotic solvent, such as diethyl ether (Et₂O), at a reduced temperature of about −78° C., as shown in step b. The epoxide of Formula 2.4 may be prepared from the ketone of Formula 2.3 using the methodology described in Scheme 1, step d, as shown in step c. The compound of Formula 2.5, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared by treating an appropriately substituted epoxide, for example the epoxide of Formula 2.4, with a nucleophile, for example 1H-tetrazole, in the presence of an organic amine base, such as diisopropyl amine, in a polar, aprotic solvent such as DMSO at an elevated temperature of about 60° C., as shown in step d.

The compound of Formula 3.5, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, may be prepared according to the methods outlined in Scheme 3, steps a-c from the appropriately substituted precursors, such as compounds of Formulae 3.0-3.1. The ketone of Formula 3.2 may be prepared by treating the Weinreb amide of Formula 3.0 with a Grignard reagent, such as the Grignard prepared via transmetalation by treating the bromopyridine of Formula 3.2 with isopropylmagnesium chloride (i-PrMgCl) in an aprotic solvent like toluene at a temperature between about 0° C. and 23° C., as shown in step a. The 4-trifluoromethylphenyl ether of Formula 3.4 may be prepared from the ketone of Formula 3.2 via treatment with the phenol of Formula 3.3 in the presence of an alkali carbonate base, for example Cs₂CO₃, in a polar solvent such as DMF at an elevated temperature of about 110° C., as shown in step b. The compound of Formula 3.5, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, may be prepared by treating an appropriately substituted ketone, for example the ketone of Formula 3.4, with a nucleophile, for example a Grignard reagent such as i-PrMgCl in the presence of zinc chloride (ZnCl₂) and lithium chloride (LiCl), in a polar, aprotic solvent like THF at a reduced temperature of about 0° C., as described by Hatano et. al. (J. Am. Chem. Soc. 2006, 128, 9998-9999) and shown in step c.

The compound of Formula 4.5, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared according to the methods outlined in Scheme 4, steps a-d from the appropriately substituted precursors, such as compounds of Formulae 4.0 and 3.2. The ketone of Formula 4.1 may be prepared by treating the Weinreb amide of Formula 4.0 and the bromopyridine of Formula 3.1 as described in Scheme 3, step a, as shown in step a. The ketone of Formula 4.3 may be prepared as described in Scheme 3, step b, from the ketone of Formula 4.1 and the phenol of Formula 4.2, as shown in step b. The epoxide of Formula 4.4 may be prepared from the ketone of Formula 4.3 using the methodology described in Scheme 1, step d, as shown in step c. The compound of Formula 4.5, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared by treating an appropriately substituted epoxide, for example the epoxide of Formula 4.4, with a nucleophile, for example 1H-tetrazole, in the presence of an organic amine base, such as diisopropyl amine, in a polar, aprotic solvent such as DMF at an elevated temperature of about 70° C., as shown in step d.

The compounds of Formula 5.1, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, may be prepared as shown in Scheme 5, step a by treating an appropriately substituted ketone, for example the ketone of Formula 5.0, with a nucleophile, for example an appropriately substituted Grignard reagent in a polar, aprotic solvent like THF at a reduced temperature of about 0° C. The Grignard reagent may be prepared from (chloromethyl)cyclopropane and magnesium (Mg) in the presence of catalytic iodine (I₂) in a polar, aprotic solvent like THF at an elevated temperature of about 65° C.

The compound of Formula 6.8, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared as shown in Scheme 6, steps c-d from the appropriately substituted precursors, such as compounds of Formulae 6.0-6.4, which may be prepared according to the methods outlined in Scheme 6, step a-b. The compound of Formula 6.5 may be prepared using methodology reported by Journet et. al. (Tet. Lett. 1998, 39, 1717-1720), which describes the preparation of the phosphonate compound of Formula 6.3 and its subsequent use in a Homer-Emmons condensation with the pyrimidine carbaldehyde of Formula 6.4, as shown in steps a and b. The compound of Formula 6.7 may be prepared via a Suzuki coupling between the bromopyridine of Formula 6.5 and an appropriately substituted boronic acid or boronate ester, for example the boronic acid of Formula 6.6, in the presence of an alkali carbonate base, such as sodium carbonate (Na₂CO₃), and a palladium catalyst, such as [1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloride [PdCl₂(dppf)], in a mixed solvent system, such as a polar, aprotic solvent, for example dioxane or acetonitrile (CH₃CN), mixed with water, wherein the ratio of organic solvent to water in the composition is about 3:1, at an elevated temperature of about 85° C., as shown in step c. The compound of Formula 6.8, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared by treating an appropriately substituted ketone, for example the ketone of Formula 6.7, with a nucleophile, for example a Grignard reagent like methyl magnesium bromide (MeMgBr), in a polar, aprotic solvent such as THF at a reduced temperature of about −78° C., as shown in step d.

The compound of Formula 7.6, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared as shown in Scheme 7, steps a-e. The bromopyridine of Formula 7.2 may be prepared via a Suzuki coupling between an appropriately substituted aryl halide, such as the iodobenzene of Formula 7.0 and a boronic acid or boronate ester, such as the pyridine boronic acid of Formula 7.1, in the presence of an alkali carbonate base, such as K₂CO₃, and a palladium catalyst, such as tetrakis(triphenylphosphine)palladium (0) [Pd(PPh₃)₄], in a polar solvent system, such as a polar, aprotic solvent, for example DMF, dioxane, or CH₃CN, mixed with water, wherein the ratio of organic solvent to water in the composition is about 4:1. The reaction is run at an elevated temperature of about 120° C., which may be achieved through conventional heating techniques or via microwave irradiation, as shown in step a. The secondary alcohol of Formula 7.3 may be prepared via metalation chemistry wherein a mixture of the bromopyridine of Formula 7.2 and excess pivaldehydeis treated with n-BuLi at a reduced temperature of about −78° C. in an aromatic hydrocarbon such as toluene, as shown in step b. The ketone of Formula 7.4 may be prepared by treating the secondary alcohol of Formula 7.3 with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) in a halogenated hydrocarbon, such as methylene chloride (CH₂Cl₂, DCM) at a reduced temperature of about 0° C., as shown in step c. The epoxide of Formula 7.5 may be prepared from the ketone of Formula 7.4 using the methodology described in Scheme 1, step d, as shown in step d. The compound of Formula 7.6, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared by treating an appropriately substituted epoxide, for example the epoxide of Formula 7.5, with a nucleophile, for example 1H-tetrazole, in the presence of an alkali carbonate base, such as K₂CO₃, in a polar, aprotic solvent like DMSO at an elevated temperature of about 70° C., as shown in step e.

The compound of Formula 8.1, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, may be prepared as shown in Scheme 8, steps a-b. The ketone of Formula 8.0 may be prepared as described in Scheme 3, step a. The compound of Formula 8.1, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, may be prepared by treating an appropriately substituted ketone, for example the ketone of Formula 8.0, with a nucleophile, for example a Grignard reagent, such as tert-butylmagnesium chloride (^(t)BuMgCl), in the presence of ZnCl₂ and LiCl, in a polar, aprotic solvent like THF at a reduced temperature of about 0° C., as shown in step b.

The compound of Formula 9.4, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared as shown in Scheme 9, steps a-e. The pyridyl carbaldehyde of Formula 9.0 may be prepared via metalation chemistry, wherein a solution of the bromopyridine of Formula 7.2 in an aromatic hydrocarbon, such as toluene, is treated with n-BuLi at a reduced temperature of about −78° C. and the subsequent lithiopyridine is quenched with anhydrous DMF, as shown in step a. The secondary alcohol of Formula 9.1 may be prepared by treating a solution of the aldehyde of Formula 9.0 in an aprotic solvent like Et₂O with a nucleophile, such as a Grignard reagent, which may be prepared by treating an appropriately substituted benzyl bromide, such as 4-chloro-2-fluorobenzyl bromide, with Mg powder in an aprotic solvent like Et₂O, as shown in step b. The ketone of Formula 9.2 may be prepared via the oxidation of the secondary alcohol of Formula 9.1 using Dess-Martin periodinane under the conditions described in Scheme 7, step c, as shown in step c. The epoxide of Formula 9.3 may be prepared from the ketone of Formula 9.2 using the methodology described in Scheme 1, step d, as shown in step d, but using an alcohol such as tert-butanol (^(t)BuOH) as the reaction solvent. The compound of Formula 9.4, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared by treating an appropriately substituted epoxide, for example the epoxide of Formula 9.3, with a nucleophile, for example 1H-tetrazole, using the conditions described in Scheme 7, step e, as shown in step e.

The compounds of Formulae 10.0 and 10.1, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, may be prepared as shown in Scheme 10, step a. The alkyne of Formula 10.0 may be prepared by treating a solution of an appropriately substituted ketone, such as the ketone of Formula 5.0, in a polar, aprotic solvent like THF, with an appropriately substituted nucleophile, such as an acetylide anion, at a reduced temperature of about 0° C. The acetylide anion may be prepared by treating an appropriately substituted terminal alkyne, such as 3,3-dimethylbut-1-yne with a Grignard reagent, for example ethylmagnesium bromide (EtMgBr), in a polar, aprotic solvent like THF at a temperature of about 0° C. during the Grignard addition and about 40° C. following the addition. The compound of Formula 10.1 is simply the addition of residual Grignard, namely EtMgBr, into the ketone of Formula 5.0 as described in Scheme 5, step a.

The compound of Formula 11.0, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, may be prepared as shown in Scheme 10, step a, by treating a solution of an appropriately substituted ketone, such as the ketone of Formula 5.0, in an aprotic solvent like Et₂O, with an appropriately substituted nucleophile, such as a Grignard Reagent, at a reduced temperature of about 0° C. The Grignard reagent may be prepared by treating an appropriately substituted benzyl bromide, such as 1-(bromomethyl)-4-chloro-2-fluorobenzene, with Mg in an aprotic solvent like Et₂O at a temperature of about 23° C. to about 35° C.

The compound of Formula 12.8, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared according to the methods outlined in Scheme 12, steps c-f from the appropriately substituted precursors, such as compounds of Formulae 12.0-12.3, which may be prepared according to the methods outlined in Scheme 12, steps a-b. The ether of Formula 12.2 may be prepared by treating a mixture of the suitably electron deficient 4-fluorobenzonitrile of Formula 12.0 with an appropriately substituted phenol, such as the phenol of Formula 12.1, with an alkali carbonate base, such as K₂CO₃, in a polar, aprotic solvent such as DMSO at an elevated temperature of about 120° C., as shown in step a. The aldehyde of Formula 12.3 may be prepared by treating a solution of the nitrile of Formula 12.2 in a polar, aprotic solvent like THF with a reducing agent, for example diisobutylaluminum hydride (DIBAL-H), at a reduced temperature of about −78° C., as shown in step b. The secondary alcohol of formula 12.5 may be prepared by treating a solution of the aldehyde of Formula 12.3 in an aprotic solvent like Et₂O, with an appropriately substituted nucleophile, such as a Grignard reagent, at a reduced temperature of about 0° C., wherein the Grignard reagent may be prepared by treating an appropriately substituted benzyl bromide, such as 1-(bromomethyl)-4-chloro-2-fluorobenzene (Formula 12.4), with Mg in an aprotic solvent like Et₂O at a temperature of about 23° C. to about 35° C., as shown in step c. The ketone of Formula 12.6 may be prepared via the oxidation of the secondary alcohol of Formula 12.5 using Dess-Martin periodinane under the conditions described in Scheme 7, step c, as shown in step d. The epoxide of Formula 12.7 may be prepared by treating a solution of the ketone of Formula 12.6 in an aprotic solvent like Et₂O with diazomethane at a reduced temperature of about 0° C., as shown in step e. The compound of Formula 12.8, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared as described in Scheme 7, step e, as shown in step f.

The compound of Formula 13.1, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, may be prepared via metallation chemistry as shown in Scheme 13, step a, by treating a mixture of a solution of an appropriately substituted ketone, such as the ketone of Formula 13.0, and an appropriately substituted aryl halide, such as 5-bromopyrimidine, in an aprotic solvent like THF with n-BuLi at a reduced temperature of about −78° C.

The compound of Formula 14.0, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 1, may be prepared as shown in Scheme 14, step a, by treating a mixture of a solution of an appropriately substituted ketone, such as the ketone of Formula 6.7, and trimethyl-(trifluoromethyl)silane, in an aprotic solvent like THF with a fluoride source, for example cesium fluoride (CsF), at a reduced temperature of about 0° C., followed by hydrolysis with a mineral acid, such as aqueous hydrogen chloride (HCl).

The compound of Formula 15.0, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, may be prepared via metallation chemistry as shown in Scheme 15, step a, by treating a solution of an appropriately substituted ketone, such as the ketone of Formula 8.0, in an aprotic solvent like Et₂O at a reduced temperature of about −78° C. with an appropriately substituted nucleophile, such as the lithiobenzene prepared by treating a solution of an appropriately substituted aryl bromide, for example 1-bromo-2,4-difluorobenzene, in an aprotic solvent like Et₂O with n-BuLi at a reduced temperature of about −78° C.

The compound of Formula 16.3 is representative of metalloenzyme inhibitors of Formula I, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, and can be prepared according to the methods outlined in Scheme 16, steps a-c. The ketone of Formula 16.1 can be prepared by treating the Weinreb amide of Formula 3.0 and the iodobromopyridine of Formula 16.0 as described in Scheme 3, step a at a temperature between about −40° C. and 23° C. in a polar, aprotic solvent like THF. The alcohol of Formula 16.2 can be prepared by treating a ketone of Formula 16.1 with a nucleophile, for example a Grignard reagent like tert-pentylmagnesium chloride, at a temperature between about −78° C. and 0° C. in a polar, aprotic solvent like THF ashown in step b. Alternatively, metallation chemistry utilizing alkyl- or aryllithium reagents can also be used to give alcohols represented by Formula 16.2, as described in Scheme 15, step a. The alcohol of Formula 16.3 can be prepared from the alcohol of Formula 16.2 and a boronic acid, a boronate ester, or an N-methyliminodiacetic acid (MIDA) boronate using the Suzuki coupling methodology described in Scheme 7, step a, or with a modified Suzuki coupling procedure as described in Angew. Chem. Int. Ed. 2012, 51, 2667, as shown in step c.

The compounds of Formulae 17.1 and 17.2 are representative of metalloenzyme inhibitors of Formula I, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, and can be prepared according to the methods outlined in Scheme 17, step a. The E and Z oxime isomers, compounds of Formulae 17.1 and 17.2 respectively, can be prepared by treating a ketone of Formula 17.0 with a base, such as sodium acetate (NaOAc), and an amine, such as O-methylhydroxylamine hydrochloride, in a polar, protic solvent like methanol (MeOH) at about 22° C., as shown in step a.

The compound of Formula 18.1 is representative of metalloenzyme inhibitors of Formula I, wherein R₁-R₃, R₅-R₇, and Z are as originally defined and n is 0, and can be prepared according to the methods outlined in Scheme 18. The compound of Formula 18.1 can be prepared by treating a compound of Formula 18.0 with an iodinating reagent, such as chloroiodomethane (CH₂Cl), in a halogenated hydrocarbon like DCM, at a temperature of about 23° C., as shown in step a.

Examples Example 1: Preparation of 4-((6-(1-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propan-2-yl)pyridin-3-yl)oxy)benzonitrile (1)

Step A1: Preparation of ethyl 2-(2,4-difluorophenyl)-2,2-difluoroacetate

To a stirred suspension of copper metal (Cu, 10.59 grams (g), 166.6 millimole (mmol)) in anhydrous DMSO (80 milliliters (mL)) was added ethyl 2,2-difluoro-2-bromoacetate (16.9 g, 83.3 mmol) and the solution was stirred for 90 minutes (min) at room temperature. To this solution was added a solution of 2,4-difluoroiodobenzene (10.0 g, 41.7 mmol) in DMSO (10 mL) and the reaction mixture was stirred at room temperature for 48 hours (h). The reaction mixture was diluted with ethyl acetate (EtOAc, 800 mL), filtered through a pad of Celite®, and the filtrate was washed successively with 5% aqueous ammonium hydroxide (NH₄OH), saturated aqueous ammonium chloride (NH₄Cl) solution, and saturated aqueous sodium chloride (NaCl, brine) solution. The organic phase was dried over sodium sulfate (Na₂SO₄), filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel, SiO₂) to afford the title compound (7.9 g, 80%).

Step A2: Preparation of 4-(6-bromopyridin-3-yloxy)benzonitrile

To a stirred suspension of 2-bromo-5-hydroxypyridine (10.0 g, 62.1 mmol) and 4-fluorobenzonitrile (11.21 g, 93.10 mmol) in DMF (125 mL) was added Cs₂CO₃ (40.44 g, 124.1 mmol) at room temperature under a nitrogen gas (N₂) atmosphere, and the reaction mixture was heated to 90° C. and stirred at 90° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with ice water, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (SiO₂) to afford the title compound (9.5 g, 55%).

Step B: Preparation of 4-(6-(2-(2,4-difluorophenyl)-2,2-difluoroacetyl)pyridin-3-yloxy)benzonitrile

To a stirred suspension of 4-(6-bromopyridin-3-yloxy)benzonitrile (1 g, 3.63 mmol) in anhydrous toluene (10 mL) was added a solution of n-BuLi in hexane (2.5 Molar (M), 4.36 mL, 10.9 mmol) dropwise at −78° C. over a 10 min period and the mixture was stirred at −78° C. for 2 h. The reaction mixture was treated with a solution of ethyl 2-(2,4-difluorophenyl)-2,2-difluoroacetate (1.71 g, 7.26 mmol) in toluene (10 mL), and the mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with 1 Normal (N) aqueous HCl solution and extracted with EtOAc. The organic extract was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound (1.75 g) which was used in the next step without further purification.

Step C: Preparation of 4-(6-(2-(2,4-difluorophenyl)difluoromethyl)oxiran-2-yl)pyridine-3-yloxy)benzonitrile

To a stirred suspension of trimethylsulfoxonium iodide (660 milligrams (mg), 3.02 mmol) in a mixture of anhydrous THF (10 mL) and DMSO (4 mL) at 0° C. was added potassium-tert-butoxide (KO^(t)Bu, 339 mg, 3.02 mmol) and the mixture was stirred for 90 min at 0° C. The reaction was cooled to −20° C. and a solution of 4-(6-(2-(2,4-difluoro-phenyl)-2,2-difluoroacetyl)pyridin-3-yloxy)benzonitrile (0.9 g, 2.32 mmol) in THF (19 mL) was added dropwise to the mixture over a 10 min period. The reaction mixture was warmed to 0° C., stirred at 0° C. for 30 min, and quenched with 1 N HCl solution followed by saturated aqueous sodium bicarbonate (NaHCO₃) solution. The mixture was extracted with EtOAc, and the organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain crude product which was purified by column chromatography (SiO₂) to afford the title compound (150 mg, 10%).

Step D: Preparation of 4-((6-(1-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propan-2-yl)pyridin-3-yl)oxy)benzonitrile (1)

To a stirred solution of 4-(6-(2-(2,4-difluorophenyl)difluoromethyl)oxiran-2-yl)pyridine-3-yloxy)benzonitrile (150 mg, 0.2 mmol) in DMF (2 mL) was added 1H-tetrazole (26 mg, 0.3 mmol) and K₂CO₃ (51 mg, 0.3 mmol) and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to room temperature, quenched with ice water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure, and the resulting crude residue was purified by column chromatography (SiO₂) to give the title compound (35 mg, 20%) as pale-yellow semi-solid: See Table 2 for characterization data.

Example 2: Preparation of 2-(5-((5-chloropyridin-2-yl)oxy)pyridin-2-yl)-4-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)butan-2-ol (2)

Step A: Preparation of 3-(2,4-difluorophenyl)-N-methoxy-N-methylpropanamide

Followed an adapted procedure described by Trost, B. M. et. al. (Journal of the American Chemical Society (2010), 132(26), 8915-8917). To a magnetically stirred mixture of 3-(2,4-difluorophenyl)propanoic acid (1.0 g, 5.37 mmol), and two drops of DMF in anhydrous THF (10.8 mL) was added dropwise oxalyl chloride (0.564 mL, 6.45 mmol) under an inert atmosphere (N₂) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then the volatile components were removed by rotary evaporation under reduced pressure. The resulting oil was dissolved in CH₂Cl₂ and the volatile components were once again removed by rotary evaporation. In a separate 20 mL vial containing N,O-dimethylhydroxylamine hydrochloride (0.576 g, 5.91 mmol) suspended in CH₂Cl₂ (5.40 mL) was added pyridine (1.086 mL, 13.43 mmol), and the reaction mixture was cooled to 0° C. The freshly prepared acid chloride was dissolved in CH₂Cl₂ (5.40 mL) and the solution was added to the mixture dropwise over a 3 min period. A white precipitate formed immediately and the reaction was stirred while gradually warming to room temperature. After 2 h, the reaction mixture was diluted with EtOAc and washed successively with 2 N HCl, saturated aqueous NaHCO₃ (2×), and brine, and then dried by passing through a phase separator cartridge. The solvent and other volatile components were removed by rotary evaporation to give the title compound (1.195 g, 97%) as a light-yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.18 (m, 1H), 6.83-6.74 (m, 2H), 3.63 (s, 3H), 3.17 (s, 3H), 2.95 (t, J=7.7 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −113.29, −114.40 (d, J=6.7 Hz); ESIMS m/z 230 [M+H]⁺.

Step B: Preparation of 1-(5-((5-chloropyridin-2-yl)oxy)pyridin-2-yl)-3-(2,4-difluorophenyl)propan-1-one

To a magnetically stirred mixture of 2-bromo-5-((5-chloropyridin-2-yl)oxy)pyridine (243 mg, 0.851 mmol) in anhydrous Et₂O (2908 microliters (L)) at −78° C. was added a solution of n-BuLi in hexanes (2.0 M, 425 μL, 0.850 mmol) dropwise over a 1 min period. The reaction mixture was stirred at −78° C. for 40-60 min and then treated dropwise with a solution of 3-(2,4-difluorophenyl)-N-methoxy-N-methylpropanamide (150 mg, 0.654 mmol) in Et₂O (1454 μL). After 1 h, the reaction was quenched by the dropwise addition of 1 N HCl (5 mL) and then warmed to room temperature. The reaction was diluted with water (5 mL) and the phases were separated. The aqueous phase was extracted with additional Et₂O (2×), and the combined organics were dried by passing through a phase separator cartridge and concentrated under a gentle stream of N₂. The resulting residue was purified by column chromatography (SiO₂, 0→20% EtOAc in hexanes) to give the title compound (76 mg, 31.0%) as an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.50 (dd, J=2.7, 0.5 Hz, 1H), 8.13-8.10 (m, 2H), 7.73 (dd, J=8.7, 2.7 Hz, 1H), 7.61 (dd, J=8.6, 2.7 Hz, 1H), 7.26-7.21 (m, 1H), 7.02 (dd, J=8.7, 0.6 Hz, 1H), 6.82-6.74 (m, 2H), 3.53 (t, J=7.5 Hz, 2H), 3.06 (t, J=7.5 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −113.54 (d, J=6.8 Hz), −113.99 (d, J=6.8 Hz); ESIMS m/z 375 [M+H]⁺.

Step C: Preparation of 5-chloro-2-((6-(2-(2,4-difluorophenethyl)oxiran-2-yl)pyridin-3-yl)oxy)pyridine

To a magnetically stirred mixture of trimethylsulfoxonium iodide (103 mg, 0.468 mmol) in THF (961 μL) was added NaH (18.73 mg, 0.468 mmol, 60% dispersion in mineral oil) under an N₂ atmosphere, and the mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and treated dropwise with a solution of 1-(5-((5-chloropyridin-2-yl)oxy)pyridin-2-yl)-3-(2,4-difluorophenyl)propan-1-one (150 mg, 0.360 mmol) in THF (961 μL). After 2.5 h, the reaction was quenched by dropwise addition of saturated aqueous NH₄Cl, and the mixture was extracted with Et₂O (3×). The combined organic extracts were dried by passing through a phase separator cartridge and concentrated under a gentle stream of N₂. The resulting residue was purified by column chromatography (SiO₂, 0→30% EtOAc in hexanes) to give the title compound (56 mg, 40.0%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 8.44 (dd, J=2.7, 0.6 Hz, 1H), 8.10 (d, J=2.6 Hz, 1H), 7.72-7.67 (m, 1H), 7.48 (dd, J=8.6, 2.7 Hz, 1H), 7.39 (dd, J=8.6, 0.4 Hz, 1H), 7.18-7.10 (m, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.80-6.70 (m, 2H), 3.06 (d, J=5.2 Hz, 1H), 2.85 (d, J=5.2 Hz, 1H), 2.83-2.75 (m, 2H), 2.71 (t, J=9.8 Hz, 1H), 2.14-2.07 (m, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −113.69 (dd, J=6.6, 2.1 Hz), −114.18 (d, J=6.7 Hz); ESIMS m/z 389 [M+H]+.

Step D: Preparation of 2-(5-((5-chloropyridin-2-yl)oxy)pyridin-2-yl)-4-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)-butan-2-ol (2)

To a magnetically stirred mixture of 5-chloro-2-((6-(2-(2,4-difluorophenethyl)oxiran-2-yl)pyridin-3-yl)oxy)pyridine (56 mg, 0.144 mmol) in DMSO (480 μL) were added a mixture of diisopropylamine and 1H-tetrazole (1:1) (123 mg, 0.720 mmol), and the reaction mixture was warmed to 60° C. and stirred for 2-3 days (d) at 60° C. The reaction was quenched by the addition of water and extracted with CH₂Cl₂ (3×). The combined organic extracts were dried by passing through a phase separator cartridge and concentrated under a gentle stream of N₂. The resulting residue was purified by column chromatography (SiO₂, 20→60% EtOAc in hexanes) to yield two isomers of the product. Isolated the title compound (37.0 mg, 56%) as a white solid: See Table 2 for characterization data.

The 2H-isomer, 2-(5-((5-chloropyridin-2-yl)oxy)pyridin-2-yl)-4-(2,4-difluorophenyl)-1-(2H-tetra-zol-2-yl)butan-2-ol (19.0 mg, 28.7%) was isolated as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 8.37 (d, J=2.6 Hz, 1H), 8.11 (d, J=2.6 Hz, 1H), 7.71 (dd, J=8.7, 2.7 Hz, 1H), 7.55 (dd, J=8.6, 2.6 Hz, 1H), 7.42 (dd, J=8.6, 0.6 Hz, 1H), 7.04 (td, J=8.7, 6.6 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.77-6.67 (m, 2H), 5.19 (s, 1H), 5.04 (s, 2H), 2.80-2.70 (m, 1H), 2.43-2.30 (m, 2H), 2.12 (ddd, J=13.4, 11.9, 4.9 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −113.36 (d, J=6.7 Hz), −114.44 (d, J=6.7 Hz); ESIMS m/z 459 [M+H].

Example 3: Preparation of 2-methyl-1-(pyrimidin-5-yl)-1-(5-(4-(trifluoromethyl)-phenoxy)pyridin-2-yl)propan-1-ol (3)

Step A: Preparation of (5-fluoropyridin-2-yl)(pyrimidin-5-yl)methanone

To a round bottomed flask equipped with a magnetic stir bar was added 2-bromo-5-fluoropyridine (2.063 g, 11.72 mmol) and the flask was purged with N₂. Anhydrous toluene (11.17 mL) was added and the reaction was cooled to 0° C. in an ice bath. The reaction was treated with a solution of i-PrMgCl in THF (2.0 M, 5.86 mL, 11.7 mmol) dropwise, and the mixture was stirred at 0° C. for 10 min, warmed to room temperature, and stirred at room temperature for 1.5 h. The resulting dark brown mixture was cooled to 0° C., treated with a solution of N-methoxy-N-methylpyrimidine-5-carboxamide (1.4 g, 8.37 mmol) in anhydrous toluene (5.58 mL), stirred at 0° C. for 3 h, and the resulting green-brown mixture was quenched with saturated aqueous NH₄Cl solution (20 mL) while cold. The phases were separated and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organics were dried over magnesium sulfate (MgSO₄), filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→50% EtOAc in hexanes) to give the title compound (492 mg, 32%) as an off-white, fluffy solid: IR (Thin Film) 1678, 1577 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.50 (s, 2H), 9.38 (s, 1H), 8.59 (dd, J=2.8, 0.6 Hz, 1H), 8.32 (ddd, J=8.8, 4.6, 0.6 Hz, 1H), 7.66 (ddd, J=8.8, 7.9, 2.8 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −117.71; HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₀H₇FN₃O, 204.0568; found, 204.0567.

Step B: Preparation of pyrimidin-5-yl(5-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)methanone

A magnetically stirred mixture of (5-fluoropyridin-2-yl)(pyrimidin-5-yl)methanone (200 mg, 0.984 mmol), 4-(trifluoromethyl)phenol (160 mg, 0.984 mmol), and Cs₂CO₃ (337 mg, 1.034 mmol) in DMF (1969 μL) was heated to 110° C. and stirred for 18 h. The reaction was cooled to room temperature, partitioned between water (3 mL) and EtOAc (3 mL), and the phases were separated. The aqueous phase was extracted with additional EtOAc (2×3 mL), and the combined organic extracts were washed with brine (2×3 mL), dried over MgSO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→60% EtOAc in hexanes) to give the title compound (290 mg, 84%) as a slightly yellow solid: IR (Thin Film) 3383, 1667, 1573, 1319, 1234 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.51 (s, 2H), 9.37 (s, 1H), 8.50 (dd, J=2.8, 0.6 Hz, 1H), 8.28 (dd, J=8.7, 0.6 Hz, 1H), 7.78-7.68 (m, 2H), 7.49 (dd, J=8.7, 2.8 Hz, 1H), 7.25-7.19 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.13; HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₇H₁₁F₃N₃O₂, 346.0798; found, 346.0780.

Step C: Preparation of 2-methyl-1-(pyrimidin-5-yl)-1-(5-(4-(trifluoromethyl)-phenoxy)pyridin-2-yl)propan-1-ol (3)

To a vial equipped with a magnetic stir bar were added ZnCl₂ (10.66 mg, 0.078 mmol) and LiCl (12.16 mg, 0.287 mmol) and the vial was capped and purged with N₂. A solution of i-PrMgCl in THF (2.0 M, 222 μL, 0.443 mmol) was added dropwise under N₂ and the reaction was stirred at room temperature for 1 h. The resulting homogeneous brown solution was cooled to 0° C. in an ice bath and a solution of pyrimidin-5-yl(5-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)methanone (90 mg, 0.261 mmol) in anhydrous THF (2738 μL) was added slowly and the reaction was stirred at 0° C. for 4 h. The resulting red-brown reaction mixture was quenched while cold with saturated aqueous NH₄Cl solution (3 mL) and the mixture was extracted with EtOAc (3×5 mL). The combined extracts were dried over MgSO₄, filtered, concentrated, and the residue was purified by column chromatography (SiO₂, 0→70% EtOAc in hexanes) to give the title compound (64 mg, 62%) as a slightly yellow, viscous oil: See Table 2 for characterization data.

Example 4: Preparation of 4-((6-(1-cyclopropyl-1-hydroxy-2-(1H-tetrazol-1-yl)ethyl)pyridin-3-yl)oxy)benzonitrile (19)

Step A: Preparation of cyclopropyl(5-fluoropyridin-2-yl)methanone

The title compound was prepared from 2-bromo-5-fluoropyridine and N-methoxy-N-methyl-cyclopropanecarboxamide according to the conditions described in Example 3A and was isolated as a yellow oil in 73% yield: IR (Thin Film) 1681, 1580, 1400, 1370 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.55 (d, J=2.8 Hz, 1H), 8.10 (ddd, J=8.7, 4.7, 0.6 Hz, 1H), 7.52 (ddd, J=8.7, 8.0, 2.8 Hz, 1H), 3.55-3.39 (m, 1H), 1.28-1.22 (m, 2H), 1.15-1.08 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −120.55 (d, J=1.5 Hz); EIMS (m/z) 165.

Step B: Preparation of 4-((6-(cyclopropanecarbonyl)pyridin-3-yl)oxy)benzonitrile

The title compound was prepared from cyclopropyl(5-fluoropyridin-2-yl)methanone and 4-hydroxybenzonitrile according to the conditions described in Example 3B. It was isolated as a light-yellow solid in 83% yield: IR (Thin Film) 2228, 1676, 1576, 1499, 1246 cm⁻1; ¹H NMR (400 MHz, CDCl₃) δ 8.50 (dd, J=2.7, 0.7 Hz, 1H), 8.10 (dd, J=8.6, 0.7 Hz, 1H), 7.75-7.67 (m, 2H), 7.45 (dd, J=8.6, 2.8 Hz, 1H), 7.16-7.10 (m, 2H), 3.47 (tt, J=7.9, 4.7 Hz, 1H), 1.30-1.21 (m, 2H), 1.15-1.09 (m, 2H); HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₆H₁₃N₂O₂, 265.0972; found, 265.0957.

Step C: Preparation of 4-((6-(cyclopropyl(hydroxy)(pyrimidin-5-yl)methyl)pyridin-3-yl)oxy)benzonitrile

To a vial equipped with a magnetic stir bar were added trimethylsulfoxonium iodide (100 mg, 0.454 mmol), DMSO (841 μL), and anhydrous THF (841 μL). To the resulting mixture was added NaH (60% dispersion in mineral oil, 18.2 mg, 0.454 mmol) and the reaction was stirred at room temperature for 1 h. After gas evolution had ceased, the cloudy-white mixture was cooled to 0° C. and treated dropwise with a solution of 4-((6-(cyclopropanecarbonyl)pyridin-3-yl)oxy)-benzonitrile (100 mg, 0.378 mmol) in anhydrous THF (841 μL). The resulting cloudy, light-yellow mixture was slowly warmed to room temperature and the reaction was quenched with water (3 mL) and diluted with EtOAc (3 mL). The phases were separated and the aqueous layer was further extracted with EtOAc (3×3 mL). The combined organic extracts were dried over MgSO₄, filtered, concentrated, and the residue purified by column chromatography (SiO₂, 0→15% EtOAc in hexanes) to give the title compound (72 mg, 65%) as a light-yellow, viscous oil: IR (Thin Film) 2228, 1502, 1479, 1247 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.43 (dd, J=2.8, 0.7 Hz, 1H), 7.68-7.61 (m, 2H), 7.54 (dd, J=8.6, 0.7 Hz, 1H), 7.38 (dd, J=8.6, 2.8 Hz, 1H), 7.08-7.01 (m, 2H), 3.00 (dd, J=5.8, 0.6 Hz, 1H), 2.95 (d, J=5.7 Hz, 1H), 1.85 (tt, J=8.4, 5.3 Hz, 1H), 0.67-0.58 (m, 1H), 0.58-0.49 (m, 1H), 0.49-0.38 (m, 2H); HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₇H₁₅N₂O₂, 279.1128; found, 279.1105.

Step D: 4-((6-(1-cyclopropyl-1-hydroxy-2-(1H-tetrazol-1-yl)ethyl)pyridin-3-yl)oxy)-benzonitrile (19)

To a vial equipped with a magnetic stir bar were added 4-((6-(2-cyclopropyloxiran-2-yl)pyridin-3-yl)oxy)benzonitrile (69 mg, 0.248 mmol), diisopropylammonium tetrazol-1-ide (212 mg, 1.24 mmol), and DMF (1653 μL). The reaction mixture was warmed to 70° C., stirred at 70° C. for 13 h, cooled to room temperature, and partitioned between water (5 mL) and EtOAc (5 mL). The phases were separated and the aqueous phase was further extracted with EtOAc (3×3 mL). The combined organics were dried over MgSO4, filtered, concentrated, and purified by column chromatography (SiO₂, 0→75% EtOAc in hexanes) to give the title compound (11 mg, 12%) as an off-white, viscous semi-solid: See Table 2 for characterization data.

Example 5: Preparation of 1-(5-(4-chlorophenoxy)pyridine-2-yl)-1-(pyrimidin-5-yl)pent-4-en-1-ol (21)

To an oven-dried vial equipped with a magnetic stir bar was added Mg (6.36 mg, 0.262 mmol) and the vial was evacuated and backfilled with N₂. Anhydrous THF (818 μL) was added followed by a crystal of I₂ and (chloromethyl)cyclopropane (22.68 μL, 0.245 mmol). The mixture was heated to reflux and stirred for 1.5 h under N₂. To a separate vial were added (5-(4-chlorophenoxy)pyridin-2-yl)(pyrimidin-5-yl)methanone (51 mg, 0.164 mmol) and anhydrous THF (1 mL) and to the mixture was cooled to 0° C. To this solution was added the freshly prepared Grignard solution dropwise over an 8 min period, and the reaction mixture was stirred at 0° C. for 3 h, quenched while cold with saturated aqueous NH₄Cl solution (2 mL), and warmed to room temperature. The mixture was extracted with EtOAc (3×2 mL) and the combined extracts were dried over MgSO₄, filtered, concentrated, and the residue purified by column chromatography (SiO₂, 0→70% EtOAc in hexanes) to give the title compound (22 mg, 35%) as a light-yellow, viscous semi-solid: See Table 2 for characterization data.

Example 6: Preparation of 2-[5-(4-chlorophenyl)-2-pyridyl]-1-pyrimidin-5-yl-propan-2-ol (25)

Step A: Preparation of diphenyl ((5-bromopyridin-2-yl)(phenylamino)methyl)-phosphonate

Followed an adapted procedure described by Journet, M., et. al. (Tetrahdron Letters (1998), 39(13), 1717-1720). To a magnetically stirred mixture of 5-bromopicolinaldehyde (1 g, 5.38 mmol) in isopropyl alcohol (IPA, 13.44 mL) was added aniline (0.589 mL, 6.45 mmol) followed by diphenyl phosphite (1.665 mL, 8.60 mmol) and the reaction mixture was stirred at 25° C. Upon addition of the aniline to the partially dissolved aldehyde in IPA, the reaction formed a thick white precipitate which dissolved upon addition of the phosphite to give a homogeneous yellow solution which was stirred for 18 h. The stirrer was stopped and the reaction mixture was cooled in an ice bath. The resulting fine, white precipitate was isolated by vacuum filtration and washed several times with ice cold IPA. The solid was dried in a vacuum oven at room temperature for 4 h to give the title compound (2.501 g, 94%) as a white solid: mp 124-127° C.: ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J=2.3 Hz, 1H), 7.76 (ddd, J=8.4, 2.3, 0.7 Hz, 1H), 7.48-7.45 (m, 1H), 7.30-7.22 (m, 4H), 7.19-7.11 (m, 4H), 7.09 (qd, J=2.5, 1.3 Hz, 2H), 7.06-7.01 (m, 2H), 6.80-6.74 (m, 1H), 6.71 (dd, J=8.6, 0.9 Hz, 2H), 5.35-5.23 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 153.41, 150.59, 150.56, 150.22, 150.14, 145.93, 145.80, 139.42, 139.40, 129.71, 129.33, 125.44, 125.32, 124.42, 124.38, 120.63, 120.58, 120.32, 120.28, 119.25, 114.31, 58.37, 56.83.

Step B: Preparation of 1-(5-bromopyridin-2-yl)-2-(pyrimidin-5-yl)ethanone

To a magnetically stirred mixture of diphenyl ((5-bromopyridin-2-yl)(phenylamino)-methyl)phosphonate (400 mg, 0.808 mmol), and pyrimidine-5-carbaldehyde (96 mg, 0.888 mmol) in a mixture of THF (1615 μL) and IPA (404 μL) was added Cs₂CO₃ (342 mg, 1.050 mmol) under an inert atmosphere (N₂). The reaction mixture was stirred at 25° C. for 16.5 h and then treated dropwise with 3 N HCl (0.81 mL, 2.42 mmol), which produced a gentle evolution of gas. After 2 h, the pH of the reaction mixture was adjusted to 9 by the addition of 5% w/v aqueous NaOH solution and extracted with EtOAc (3×). The combined organic extracts were dried by passing through a phase separator cartridge and the volatile components were evaporated under a gentle stream of N₂. The resulting residue was triturated with ice cold EtOAc to give the title compound (149 mg, 66.3%) as a light brown solid: ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.79 (d, J=1.7 Hz, 1H), 8.72 (s, 2H), 8.02 (dd, J=8.4, 2.2 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 4.52 (s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 196.19, 157.96, 157.40, 150.47, 150.37, 139.98, 128.33, 126.16, 123.66, 38.86; ESIMS m/z 278 [M+H]⁺, m/z 276 ([M−H]⁻).

Step C: Preparation of 1-(5-(4-chlorophenyl)pyridin-2-yl)-2-(pyrimidin-5-yl)ethanone

To a magnetically stirred mixture of 1-(5-bromopyridin-2-yl)-2-(pyrimidin-5-yl)ethanone (200 mg, 0.719 mmol), (4-chlorophenyl)boronic acid (141 mg, 0.899 mmol) and Na₂CO₃ (229 mg, 2.16 mmol) in a mixture of dioxane (2697 μL) and water (899 μL) was added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (PdCl₂(dppf), 52.6 mg, 0.072 mmol) under an inert atmosphere (N₂). The reaction mixture was heated to and stirred at 85° C. for 17 h, cooled to room temperature, diluted with CH₃CN, filtered through a pad of Celite®, and the filtrate was evaporated under a gentle stream of N₂. The resulting residue was purified by column chromatography (SiO₂, 30→75% EtOAc in hexanes) to yield the title compound (116 mg, 52.1%) as an off-white solid: mp 150-155° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.92 (dd, J=2.3, 0.8 Hz, 1H), 8.76 (s, 2H), 8.16 (dd, J=8.1, 0.8 Hz, 1H), 8.02 (dd, J=8.2, 2.3 Hz, 1H), 7.60-7.56 (m, 2H), 7.53-7.49 (m, 2H), 4.59 (s, 2H); ESIMS m/z 310 [M+H]⁺, m/z 308 ([M−H]⁻).

Step D: Preparation of 2-(5-(4-chlorophenyl)pyridin-2-yl)-1-(pyrimidin-5-yl)propan-2-ol (25)

To a magnetically stirred mixture of 1-(5-(4-chlorophenyl)pyridin-2-yl)-2-(pyrimidin-5-yl)ethanone (50 mg, 0.161 mmol) in THF (1614 μL) cooled to −78° C. was added a solution of MeMgBr in Et₂O (3.0 M, 108 μL, 0.323 mmol) dropwise under an N₂ atmosphere. The reaction mixture was stirred at −78° C. for 105 min and quenched by the dropwise addition of saturated aqueous NH₄Cl (2 mL). The reaction mixture was removed from the cooling bath, warmed to room temperature, diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried by passing through a phase separator cartridge and the volatile components were evaporated under a gentle stream of N₂. The resulting residue was adsorbed onto a pad of Celite® and purified by column chromatography (SiO₂, 50→80% EtOAc in hexanes) to yield recovered starting material (42%) and the title compound (19 mg, 36.1%) as a light-yellow solid: See Table 2 for characterization data.

Steps C and D may be conducted in either order to obtain desired product.

Example 7: Preparation of 3,3-dimethyl-1-(1H-tetrazol-1-yl)-2-[5-[4-(trifluoro-methoxy)phenyl]pyridine-2-yl]butan-2-ol (26)

Step A: Preparation of 2-bromo-5-(4-(trifluoromethoxy)phenyl)pyridine

To a microwave vial equipped with a magnetic stir bar were added (6-bromopyridin-3-yl)boronic acid (1.37 g, 6.77 mmol), 1-iodo-4-(trifluoromethoxy)benzene (1.5 g, 5.21 mmol) and DMF (11.9 mL), followed by K₂CO₃ (2.52 g, 18.2 mmol) and water (2.98 mL). The reaction mixture was stirred under N₂ for 5 min and treated with Pd(PPh₃)₄(16.05 mg, 0.014 mmol). The reaction vessel was capped, placed in a Biotage Initiator microwave reactor for 1 h at 120° C., with external IR-sensor temperature monitoring from the side of the vessel. The cooled reaction mixture was filtered through a pad of Celite® rinsing with EtOAc (100 mL), and the filtrate was washed successively with saturated aqueous NaHCO₃ (50 mL), water (3×50 mL), and brine (50 mL). The organic phase was dried over MgSO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→10% EtOAc in hexanes) to give the title compound (1.07 g, 63%) as an off-white solid: IR (Thin Film) 3036, 1453, 1210, 1167 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.57 (dd, J=2.6, 0.8 Hz, 1H), 7.71 (dd, J=8.2, 2.6 Hz, 1H), 7.63-7.54 (m, 3H), 7.38-7.29 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −57.83; HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₂H₈BrF₃NO, 317.9736; found, 317.9735.

Step B: Preparation of 2,2-dimethyl-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-1-ol

To a solution of 2-bromo-5-(4-(trifluoromethoxy)phenyl)pyridine (2 g, 6.32 mmol) and pivaldehyde (2 mL, 12.5 mmol) in toluene (20 mL) was added n-BuLi (10 mL, 15.8 mmol) at −78° C. and the mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH₄Cl solution, warmed to room temperature, and extracted with EtOAc. The organic extract was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 5→10% EtOAc in petroleum ether) to afford the title compound (3 g, 60% purity by LCMS) as yellow oil. The compound was used for the next step without further purification.

Step C: Preparation of 2,2-dimethyl-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-1-one

To a solution of 2,2-dimethyl-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-1-ol (3 g, 5.6 mmol, 60% purity) in anhydrous CH₂Cl₂ (30 mL) was added Dess-Martin periodinane (7.8 g, 18.4 mmol) in portions at 0° C., and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was vacuum filtered, washing with CH₂Cl₂, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 5→10% EtOAc in petroleum ether) to afford the title compound (500 mg, 25% over two steps) as an off-white solid.

Step D: Preparation of 2-(2-tert-butyloxiran-2-yl)-5-(4-(trifluoromethoxy) phenyl) pyridine

To a suspension of trimethylsulfoxonium iodide (613 mg, 2.78 mmol) in THF (5 mL) was added NaH (110 mg, 2.78 mmol, 60% dispersion in mineral oil) at 0° C. followed by DMSO (1 mL), and the reaction mixture was stirred for 1 h at 0° C. and then treated with a solution of 2,2-dimethyl-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-1-one (600 mg, 1.85 mmol) in THF. The reaction mixture was warmed to room temperature, stirred for 15 h, poured into ice water, and extracted with EtOAc. The organic extract was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 15→20% EtOAc in petroleum ether) to afford the title compound (150 mg, 24%) as yellow oil.

Step E: Preparation of 3,3-dimethyl-1-(1H-tetrazol-1-yl)-2-[5-[4-(trifluoromethoxy)phenyl]pyridine-2-yl]butan-2-ol (26)

To a solution of 2-(2-tert-butyloxiran-2-yl)-5-(4-(trifluoromethoxy) phenyl)pyridine (450 mg, 1.33 mmol) in DMSO (5 mL) was added 1H-tetrazole (187 mg, 2.67 mmol) and K₂CO₃ (276 mg, 2.0 mmol) under an inert atmosphere. The reaction mixture was heated to and stirred at 70° C. for 48 h, cooled to room temperature, poured into water, and extracted with EtOAc. The organic extract was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 5→10% EtOAc in petroleum ether) to afford the title compound (80 mg, 15%) as off-white solid: See Table 2 for characterization data.

The 2H regioisomer was also isolated (18 mg, 3%) as an off-white solid: ¹H NMR (400 MHz, CDCl₃): δ 8.61 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 7.84 (dd, J=8.3, 2.4 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 5.70 (d, J=13.4 Hz, 1H), 5.31 (brs, 1H), 5.09 (d, J=13.6 Hz, 1H), 1.09 (s, 9H); ESIMS m/z 408 [M+H]⁺.

Example 8: Preparation of 2,2-dimethyl-1-(pyrimidin-5-yl)-1-(5-(4-(trifluoro-methoxy)phenyl)pyridin-2-yl)propan-1-ol (27)

Step A: Preparation of pyrimidin-5-yl(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methanone

The title compound was prepared from 2-bromo-5-(4-(trifluoromethoxy)phenyl)-pyridine and N-methoxy-N-methylpyrimidine-5-carboxamide using the conditions described in Example 3A. Additional purification was required by reverse phase column chromatography (C₁₈, 10→100% CH₃CN in water) to give the title compound as an off-white solid in 31% yield: IR (Thin Film) 1663, 1316, 1163 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.56 (s, 2H), 9.40 (s, 1H), 8.96 (dd, J=2.3, 0.8 Hz, 1H), 8.33 (dd, J=8.2, 0.8 Hz, 1H), 8.13 (dd, J=8.2, 2.3 Hz, 1H), 7.73-7.67 (m, 2H), 7.40 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −57.77; HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₇H₁₁F₃N₃O₂, 346.0798; found, 346.0803.

Step B: Preparation of 2,2-dimethyl-1-(pyridin-3-yl)-1-(5-(4-(trifluoromethoxy)-phenyl)pyridin-2-yl)propan-1-ol (27)

To a vial equipped with a magnetic stir bar were added ZnCl₂ (14.3 mg, 0.105 mmol) and LiCl (16.3 mg, 0.384 mmol) and the head space was purged with N₂. A 1 M solution of ^(t)BuMgCl (593 μL, 0.593 mmol) in THF was added at room temperature and the reaction mixture was stirred for 1 h, cooled to 0° C., and treated with a solution of pyrimidin-5-yl(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methanone (114 mg, 0.33 mmol) in anhydrous THF (2327 μL). After 1 h at 0° C., additional ^(t)BuMgCl solution (350 μL, 0.350 mmol) was added and stirring was continued at 0° C. for an additional 1 h and quenched while cold with saturated aqueous NH₄Cl solution (2 mL). The mixture was extracted with EtOAc (3×2 mL), and the combined extracts were dried over MgSO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→45% EtOAc in hexanes to give the title compound (47.9 mg, 36%) as a bright-yellow semi-solid: See Table 2 for characterization data.

Example 9: Preparation of 1-(4-chloro-2-fluorophenyl)-3-(1H-tetrazol-1-yl)-2-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-2-ol (28)

Step A: Preparation of 5-(4-(trifluoromethoxy)phenyl)picolinaldehyde

To a solution of 2-bromo-5-(4-(trifluoromethoxy)phenyl)pyridine (5.00 g, 15.8 mmol) in toluene (50 mL) was added n-BuLi (2.5 M in hexanes, 16 mL, 39.5 mmol) dropwise at −78° C. and the reaction mixture was stirred for 15 min, treated dropwise with anhydrous DMF (6 mL, 79.1 mmol), and stirred for 1 h at −78° C. The reaction mixture was quenched with saturated aqueous NH₄Cl solution, warmed to room temperature, and extracted with EtOAc. The extract was dried over Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography (SiO₂, 5→10% EtOAc in petroleum ether) to afford the title compound (1.2 g, 29%) as yellow solid.

Step B: Preparation of 2-(4-chloro-2-fluorophenyl)-1-(5-(4-(trifluoromethoxy) phenyl)pyridin-2-yl)ethanol

To a suspension of Mg powder (291 mg, 11.2 mmol) in anhydrous Et₂O (20 mL) was slowly added 1-(bromomethyl)-4-chloro-2-fluorobenzene (2.5 g, 11.2 mmol) and the reaction mixture was stirred vigorously for 15 min (vigorous reflux was observed). This Grignard solution was added dropwise to a solution of 5-(4-(trifluoromethoxy)phenyl)picolinaldehyde (1.2 g, 4.5 mmol) in Et₂O (10 mL) at 0° C. and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice water (100 mL) and extracted with EtOAc. The extract was dried over Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography (SiO₂, 5→10% EtOAc in petroleum ether) to afford the title compound as an off-white solid (1.1 g, 59%).

Step C: Preparation of 2-(4-chloro-2-fluorophenyl)-1-(5-(4-(trifluoromethoxy)phenyl)-pyridin-2-yl)ethanone

To a solution of 2-(4-chloro-2-fluorophenyl)-1-(5-(4-(trifluoromethoxy)phenyl)-pyridin-2-yl)ethanol (1.1 g, 2.67 mmol) in anhydrous CH₂Cl₂ (20 mL) was added Dess-Martin periodinane (2.3 g, 5.35 mmol) in portions at 0° C., and the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was vacuum filtered, the cake washed with CH₂Cl₂, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 10-15% EtOAc in petroleum ether) to afford the title compound (900 mg, 83%) as an off-white solid.

Step D: Preparation of 2-(2-(4-chloro-2-fluorobenzyl)oxiran-2-yl)-5-(4-(trifluoro-methoxy)phenyl)pyridine

To a suspension of trimethylsulfoxonium iodide (320 mg, 1.45 mmol) in ^(t)BuOH (5 mL) was added potassium tert-butoxide (KO^(t)Bu, 163 mg, 1.45 mmol) at 50° C., and the reaction mixture was stirred for 30 min, treated with a solution of 2-(4-chloro-2-fluorophenyl)-1-(5-(4-(trifluoromethoxy)-phenyl)pyridin-2-yl)ethanone (400 mg, 0.96 mmol) in ^(t)BuOH (2 mL), and stirred for 16 h at 50° C. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with EtOAc. The organic extract was washed with brine, dried over Na₂SO₄, filtered, concentrated under reduced pressure, and the residue purified by column chromatography (SiO₂, 5→10% EtOAc in petroleum ether) to afford the title compound (140 mg, 24%) as yellow oil.

Step E: Preparation of 1-(4-chloro-2-fluorophenyl)-3-(1H-tetrazol-1-yl)-2-(5-(4-(trifluoromethoxy) phenyl) pyridin-2-yl) propan-2-ol (28)

To a solution of 2-(2-(4-chloro-2-fluorobenzyl)oxiran-2-yl)-5-(4-(trifluoromethoxy)-phenyl)pyridine (130 mg, 0.3 mmol) in DMSO (5 mL) was added 1H-tetrazole (43 mg, 0.6 mmol) and K₂CO₃ (63 mg, 0.45 mmol) under an inert atmosphere. The reaction mixture was heated to 70° C. and stirred for 30 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic extract was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 5→10% EtOAc in petroleum ether) to afford the title compound (23 mg, 15%) as off-white solid: See Table 2 for characterization data.

The 2H regioisomer (30 mg, 20%) was also obtained as an off white-solid: ¹H NMR (300 MHz, CDCl₃): δ 8.63 (d, J=2.2 Hz, 1H), 8.40 (s, 1H), 7.84 (dd, J=8.2, 2.3 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.2 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.16 (t, J=8.2 Hz, 1H), 7.04-6.92 (m, 2H), 5.32 (d, J=13.8 Hz, 1H), 5.10 (s, 1H), 5.06 (d, J=13.8 Hz, 1H), 3.35 (d, J=13.8 Hz, 1H), 3.26 (d, J=13.8 Hz, 1H); ESIMS m/z 494 [M+H]⁺.

Example 10: Preparation of 1-(5-(4-chlorophenoxy)pyridin-2-yl)-4,4-dimethyl-1-(pyrimidin-5-yl)pent-2-yn-1-ol (29) and 1-(5-(4-chlorophenoxy)pyridin-2-yl)-1-(pyrimidin-5-yl)propan-1-ol (30)

To a vial equipped with a magnetic stir bar was added 3,3-dimethylbut-1-yne (23.7 μL, 0.289 mmol) and the vial was purged with N₂. Anhydrous THF (0.2 mL) was added and reaction mixture was cooled to 0° C. The resulting solution was treated dropwise with a solution of EtMgBr (1.0 M, 289 μL, 0.289 mmol) in THF and the mixture was stirred at 0° C. for 15 min, warmed to and stirred at 40° C. for 2 h, and then cooled to room temperature. To a separate vial were added (5-(4-chlorophenoxy)pyridin-2-yl)(pyrimidin-5-yl)methanone (30 mg, 0.096 mmol) and THF (481 μL), and the mixture was cooled to 0° C. The freshly prepared acetylide was added dropwise and the reaction was stirred at 0° C. for 4 h. The reaction was quenched while cold with saturated aqueous NH₄Cl solution (2 mL), extracted with EtOAc (3×2 mL), and the combined extracts were dried over MgSO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→60% EtOAc in hexanes) to give the title compounds 29 and 30.

Compound 29 (17 mg, 45% yield) was isolated as a light-yellow, cloudy, viscous oil: See Table 2 for characterization data.

Compound 30 (3.6 mg, 11% yield) was isolated as a light-yellow, viscous oil: See Table 2 for characterization data.

Example 11: Preparation of 2-(4-chloro-2-fluorophenyl)-1-(5-(4-chlorophenoxy)-pyridin-2-yl)-1-(pyrimidin-5-yl)ethanol (41)

To a stirred suspension of Mg powder (0.012 g, 0.48 mmol) in Et₂O (2 mL) was slowly added 1-(bromomethyl)-4-chloro-2-fluorobenzene (0.076 g, 0.48 mmol) during which period refluxing solvent was observed. After complete addition the reaction mixture was stirred at room temperature for 30 min, and the freshly prepared Grignard reagent was added to a solution of (5-(4-chlorophenoxy) pyridin-2-yl) (pyrimidin-5-yl) methanone (from Example 3 using 4-chlorophenol in 3B; 0.1 g, 0.32 mmol) in Et₂O (3 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 30 min, quenched carefully with saturated aqueous NH₄Cl solution, and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na₂SO₄, filtered, concentrated under reduced pressure, and the residue purified by column chromatography (SiO₂) to give the title compound (10 mg, 7%) as a yellow liquid: See Table 2 for characterization data.

Example 12: Preparation of 1-(4-chloro-2-fluorophenyl)-2-(5-(4-chlorophenoxy)-pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (42)

Step A: Preparation of 5-(4-chlorophenoxy)picolinonitrile

To an oven dried round bottomed flask equipped with a magnetic stir bar were added 2-cyano-5-fluoropyridine (10 g, 81.9 mmol), 4-chlorophenol (15.7 g, 122.9 mmol), and K₂CO₃ (22.1 g, 163.8 mmol) followed by DMSO (100 mL). The reaction mixture was heated to 120° C. and stirred at 120° C. for 3 h. The reaction was cooled to room temperature, diluted with water (200 mL), and the resulting solid was collected by filtration (Buchner funnel), air dried, and washed with pentane to afford a mixture of 5-(4-chlorophenoxy)picolinonitrile and 5-(4-chlorophenoxy)picolinamide. The solid (10 g) was dissolved in THF and the resulting solution was treated with triethylamine (Et₃N, 8.14 g, 80.6 mmol), cooled to 0° C., and treated dropwise with trifluoroacetic anhydride (TFAA, 16.9 g, 80.6 mmol) over a 30 min period. The reaction mixture was stirred for 10 min, quenched with water (100 mL), and extracted with EtOAc (500 mL). The organic extract was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂) to afford the title compound (7 g, 48%).

Step B: Preparation of 5-(4-chlorophenoxy)picolinaldehyde

To a solution of 5-(4-chlorophenoxy)picolinonitrile (7 g, 30.4 mmol) in THF (70 mL) at −78° C. was added DIBAL-H (25% in toluene, 86.4 mL, 152 mmol) and the reaction mixture was stirred at −78° C. for 30 min. The reaction mixture was quenched with 2 N HCl at −78° C., warmed to room temperature, and extracted with EtOAc. The organic extract was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂) to afford the title compound (5.4 g, 76%).

Step C: Preparation of 2-(4-chloro-2-fluorophenyl)-1-(5-(4-chlorophenoxy)pyridin-2-yl)ethanol

To a stirred suspension of Mg powder (1.12 g, 46.9 mmol) in Et₂O (60 mL) was slowly added 1-(bromomethyl)-4-chloro-2-fluorobenzene (0.615 g, 5.08 mmol) during which period refluxing of solvent was observed. After complete addition, the reaction mixture was stirred at room temperature for 30 min. The freshly prepared Grignard reagent was added to a solution of 5-(4-chlorophenoxy)picolinaldehyde (5.4 g, 23.4 mmol) in Et₂O (60 mL) at 0° C. and the mixture was warmed to room temperature, stirred for 30 min, quenched with saturated aqueous NH₄Cl solution, and extracted with EtOAc (2×200 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford a residue which was purified by column chromatography (SiO₂) to give the title compound (4 g, 45%) as white solid.

Step D: Preparation of 2-(4-chloro-2-fluorophenyl)-1-(5-(4-chlorophenoxy)pyridin-2-yl)ethanone

To a solution of 2-(4-chloro-2-fluorophenyl)-1-(5-(4-chlorophenoxy)-pyridin-2-yl)ethanol (4.00 g, 10.6 mmol) in CH₂Cl₂ (40 mL) at 0° C. was added Dess-Martin periodinane (8.99 g, 21.2 mmol) in portions, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered through Celite® rinsing with CH₂Cl₂ and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂) to afford the title compound (3.6 g, 92%).

Step E: Preparation of 2-(2-(4-chloro-2-fluorobenzyl)oxiran-2-yl)-5-(4-chlorophenoxy)pyridine

To a stirred suspension of 2-(4-chloro-2-fluorophenyl)-1-(5-(4-chlorophenoxy)pyridin-2-yl)ethanone (1 g, 2.66 mmol) in Et₂O (10 mL) was slowly added diazomethane (50 mL, 0.5 M in Et₂O) at 0° C. and the mixture was stirred for 16 h at room temperature. The reaction mixture was quenched carefully with ice cold water and extracted with EtOAc. The organic extract was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give an oily residue which was purified by column chromatography (SiO₂) to afford the title compound (0.350 g, 36%).

Step F: Preparation of 1-(4-chloro-2-fluorophenyl)-2-(5-(4-chlorophenoxy)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (42)

To a stirred solution of 2-(2-(4-chloro-2-fluorobenzyl)-oxiran-2-yl)-5-(4-chlorophenoxy)pyridine (0.350 g, 8.99 mmol) in DMSO (3.5 mL) was added 1H-tetrazole (0.125 g, 17.98 mmol) followed by K₂CO₃ (0.186 g, 13.485 mmol) at room temperature under an inert atmosphere (N₂). The reaction mixture was warmed to and stirred at 60° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with ice cold water (20 mL), and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO₂) to afford the title compound (140 mg, 34%) as an off white solid: See Table 2 for characterization data.

Example 13: Preparation of 2-cyclopropyl-1-(pyrimidin-5-yl)-1-(5-(4-(trifluoromethoxy)phenoxy)pyridin-2-yl)ethanol (45)

To a vial equipped with a magnetic stir bar were added 5-bromopyrimidine (33.9 mg, 0.213 mmol) and 2-cyclopropyl-1-(5-(4-(trifluoromethoxy)phenoxy)pyridin-2-yl)ethanone (prepared from 2-cyclopropyl-N-methoxy-N-methylacetamide using conditions described in Example 3, steps A and B; 40 mg, 0.119 mmol) followed by THF (593 μL), and the reaction mixture was cooled to −78° C. and treated with a 2.5 M solution of n-BuLi (95 μL, 0.237 mmol) in hexanes. The reaction mixture was stirred at −78° C. for 2 h, quenched with 0.5 mL of 1 M HCl, and partitioned between water (2 mL) and EtOAc (2 mL). The phases were separated and the aqueous phase was further extracted with EtOAc (2×2 mL). The combined organics were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→100% EtOAc in hexanes) to give the title compound (4.1 mg, 8%) as a light-yellow, viscous oil: See Table 2 for characterization data.

Example 14: 2-(5-(4-chlorophenyl)pyridin-2-yl)-1,1,1-trifluoro-3-(pyrimidin-5-yl)propan-2-ol (46)

To a magnetically stirred mixture of 1-(5-(4-chlorophenyl)pyridin-2-yl)-2-(pyrimidin-5-yl)ethanone (50 mg, 0.161 mmol) and trimethyl(trifluoromethyl)silane (35.8 μL, 0.242 mmol) in THF (807 μL) was added CsF (4.90 mg, 0.032 mmol) at 0° C., and the reaction mixture was stirred for 85 min, quenched with 2 mL of 1 N HCl, stirred for 45 min, warmed to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic extracts were dried by passing through a phase separator cartridge. The solvents were evaporated and the resulting residue was purified by column chromatography (SiO₂, 30→60% acetone in hexanes) to yield the title compound and its corresponding TMS ether. The TMS ether was dissolved in THF (1.5 mL), treated with additional 1 N HCl (1 mL), and stirred at room temperature overnight, at which point LCMS showed complete conversion to the free hydroxy product. The reaction mixture was quenched by the addition of saturated aqueous NaHCO₃ (gas evolution observed), extracted with EtOAc (3×), and the combined organic extracts were dried by passing through a phase separator cartridge. The volatile components were removed under a gentle stream of N₂ to give the title compound (28 mg, 45.7%) as a brown oil: See Table 2 for characterization data.

Example 15: Preparation of (2,4-difluorophenyl)(pyrimidin-5-yl)(5-(4-(trifluoro-methoxy)phenyl)pyridin-2-yl)methanol (9)

To a vial equipped with a magnetic stir bar was added 1-bromo-2,4-difluorobenzene (19.9 μL, 0.176 mmol) and the vial was purged with N₂. Anhydrous Et₂O (306 μL) was added and the reaction mixture was cooled to −78° C. and treated with a solution of n-BuLi (2.5 M, 70.4 μL, 0.176 mmol) in hexane. The reaction mixture was stirred at −78° C. for 30 min and treated dropwise with a solution of pyrimidin-5-yl(5-(4-(trifluoromethoxy)phenyl)-pyridin-2-yl)methanone (Example 8A; 52.8 mg, 0.153 mmol) in anhydrous Et₂O (306 μL), rinsing with additional Et₂O (0.5 mL) and THF (1 mL). The resulting mixture was stirred at −78° C. for 2 h, warmed to and stirred at 0° C. for 1 h, and then quenched while cold with saturated aqueous NH₄Cl solution (2 mL). The mixture was extracted with EtOAc (3×2 mL) and the combined extracts were dried over MgSO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→40% EtOAc in hexanes) to give the title compound (27 mg, 37%) as an off-white, viscous semi-solid: See Table 2 for characterization data.

Example 16: Preparation of 2,2-dimethyl-1-pyrimidin-5-yl-1-[5-[4-(trifluoromethoxy)phenyl]-2-pyridyl]butan-1-ol (93)

Step A: Preparation of (5-bromopyridin-2-yl)(pyrimidin-5-yl)methanone

A round bottom flask equipped with a magnetic stir bar was charged with 5-bromo-2-iodopyridine (7.13 g, 25.1 mmol) and the flask was purged with N₂. Anhydrous THF (67 mL) was added and the reaction mixture was cooled to −40° C., treated with a 2.0 M solution of isopropylmagnesium chloride in THF (12.56 mL, 25.1 mmol) over 10 min period, and stirred at −40° C. for 1 h. The resulting cloudy, light-brown reaction mixture was treated with a solution of N-methoxy-N-methylpyrimidine-5-carboxamide (4.2 g, 25.1 mmol) in anhydrous THF (16.8 mL) over a 10 min period, stirred at −40° C. for 45 min, and warmed to room temperature. The reaction mixture was quenched with saturated (sat'd) aqueous (aq) ammonium chloride (NH₄Cl) solution (100 mL) and extracted with DCM (3×50 mL). The combined organic phases were dried over Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography (SiO₂, 0→20% EtOAc in DCM) to give the title compound (3.41 g, 50%) as a light yellow solid: IR (Thin Film) 1667, 1560, 1314 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.50 (s, 2H), 9.39 (s, 1H), 8.81 (dd, J=2.0, 1.0 Hz, 1H), 8.18-8.06 (m, 2H); HRMS-ESI (m/z) [M+H]⁺ calcd for Cl₀H₇BrN₃O, 263.9767; found, 263.9767.

Step B: Preparation of 1-(5-bromopyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)butan-1-ol

A vial equipped with a magnetic stir bar and fitted with a septum cap was purged with N₂ and charged with (5-bromopyridin-2-yl)(pyrimidin-5-yl)methanone (210 mg, 0.80 mmol) and anhydrous THF (2.6 mL). The reaction mixture was cooled to 0° C., treated dropwise with a 1 M solution of tert-pentylmagnesium chloride in Et₂O (1.19 mL, 1.193 mmol), stirred at 0° C. until complete, and quenched with sat'd aq NH₄Cl solution (5 mL). The reaction mixture was warmed to room temperature, extracted with EtOAc (3×5 mL), and the combined organic extracts were dried over MgSO₄, filtered, concentrated, and purified by column chromatography (SiO₂, 0→50% EtOAc in hexanes) to give the title compound (134 mg, 49%) as a light-tan solid: IR (Thin Film) 3233, 1556, 1459, 1412, 1362 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 2H), 9.07 (s, 1H), 8.64 (dd, J=2.4, 0.8 Hz, 1H), 7.88 (dd, J=8.6, 2.4 Hz, 1H), 7.67 (dd, J=8.6, 0.8 Hz, 1H), 5.42 (s, 1H), 1.54-1.40 (m, 1H), 1.39-1.28 (m, 1H), 0.99 (s, 6H), 0.80 (t, J=7.5 Hz, 3H); HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₅H₁₉BrN₃O, 336.0706; found, 336.0708.

Step C: Preparation of 2,2-dimethyl-1-(pyrimidin-5-yl)-1-(5-(4-(trifluoromethoxy)-phenyl)pyridin-2-yl)butan-1-ol

The title compound was prepared from 1-(5-bromopyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)butan-1-ol and (4-(trifluoromethoxy)phenyl)boronic acid according to the conditions described in Example 7A and was isolated as a light-yellow foam in 70% yield: See Table 2 for characterization data.

Example 17: Preparation of 1-(5-(2-fluoro-4-(trifluoromethoxy)phenyl)pyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol (124)

Step A: Preparation of 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a microwave vial equipped with a magnetic stir bar were added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (294 mg, 1.16 mmol), potassium acetate (KOAc; 189 mg, 1.93 mmol) and Pd(dppf)Cl₂ (70.6 mg, 0.097 mmol) and the vial was purged with N₂. The resulting mixture was treated with a solution of 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene (250 mg, 0.96 mmol) in 1,4-dioxane (3.9 mL). The reaction vessel was capped, placed in a Biotage Initiator microwave reactor for 2 h at 100° C., with external IR-sensor temperature monitoring from the side of the vessel. The cooled reaction mixture was filtered through a pad of Celite® rinsing with EtOAc, and the filtrate was washed with sat'd aq NaHCO₃ (15 mL) and brine (2×15 mL). The organic phase was dried over MgSO₄, filtered, and concentrated to a brown oil which was used without further purification: ¹H NMR (400 MHz, CDCl₃) δ 7.77 (dd, J=8.3, 6.8 Hz, 1H), 7.01 (ddd, J=8.3, 2.3, 1.1 Hz, 1H), 6.92 (ddd, J=9.6, 2.2, 1.0 Hz, 1H), 1.36 (s, 12H); EIMS m/z 306.

Step B: Preparation of 1-(5-(2-fluoro-4-(trifluoromethoxy)phenyl)pyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol

The title compound was prepared from 1-(5-bromopyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol (prepared as described in Example 16A-16B with tBuMgCl at −78° C.) and 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane according to the conditions described in Example 7A and was isolated as a white foam in 47% yield: See Table 2 for characterization data.

Example 18: Preparation of 1-(4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)phenyl)ethanone O-methyl oxime (130 and 132)

To a vial equipped with a magnetic stir bar were added 1-(4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)phenyl)ethanone (188 mg, 0.520 mmol), prepared as described in Example 16, NaOAc (51.2 mg, 0.624 mmol), O-methylhydroxylamine hydrochloride (52.1 mg, 0.624 mmol) and MeOH (3.5 mL) at room temperature, and the reaction mixture was stirred at room temperature for approximately 15 h. The reaction mixture was diluted with sat'd aq NaHCO₃ solution (10 mL), extracted with DCM (3×5 mL), and the combined organic extracts were washed with water (2×5 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→40% EtOAc in hexanes) to give (E)-1-(4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)phenyl)ethanone O-methyl oxime (154 mg, 76%) as a white solid and (Z)-1-(4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)phenyl)ethanone O-methyl oxime (14 mg, 7%) as a white solid: See Table 2 for characterization data.

Example 19: Preparation of 5-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)thiophene-2-carboxamide(133)

The title compound was prepared from 1-(5-bromopyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbonitrile according to the conditions described in Example 7A and was isolated as a white solid in 10% yield: See Table 2 for characterization data.

Example 20: Preparation of 2-(3-fluorophenyl)-1-pyrimidin-5-yl-1-[5-[4-(trifluoromethoxy)-phenyl]-2-pyridyl]ethanol (139)

Step A: Preparation of 1-(5-bromopyridin-2-yl)-2-(3-fluorophenyl)-1-(pyrimidin-5-yl)ethanol

To an oven-dried vial equipped with a magnetic stir bar was added magnesium metal (Mg) which had been washed with 2 N HCl and dried (18.0 mg, 0.74 mmol) and the vial was purged with N₂. A crystal of I₂ was added and the mixture was diluted with anhydrous Et₂O (1.4 mL) and treated with 1-(bromomethyl)-3-fluorobenzene (91 μL, 0.74 mmol) at a rate such that no bubbling from the Mg was observed. The reaction vessel was periodically warmed allowing for gentle reflux until the I₂ color dissipated and most of the Mg was consumed. The reaction mixture was cooled to room temperature and stirred vigorously for 30. To a separate vial were added (5-bromopyridin-2-yl)(pyrimidin-5-yl)methanone (150 mg, 0.57 mmol) and anhydrous THF (2.8 mL). The resulting solution was cooled to 0° C., and the freshly prepared Grignard solution was slowly transferred to the flask containing the ketone, rinsing with additional anhydrous THF (1.4 mL). The mixture was stirred at 0° C. for 3 h and allowed to warm to room temperature as the ice melted. After 5 h, the reaction mixture was quenched with saturated aqueous (sat'd aq) NH₄Cl (5 mL), and extracted with EtOAc (3×3 mL). The combined extracts were dried over MgSO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→60% EtOAc in hexanes) to afford the title compound (112 mg, 52%) as a light-yellow, viscous oil: ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.95 (s, 2H), 8.59 (dd, J=2.3, 0.8 Hz, 1H), 7.84 (dd, J=8.4, 2.3 Hz, 1H), 7.38 (dd, J=8.4, 0.8 Hz, 1H), 7.20-7.08 (m, 1H), 6.89 (tdd, J=8.4, 2.6, 1.0 Hz, 1H), 6.82-6.72 (m, 2H), 4.67 (s, 1H), 3.75 (d, J=13.6 Hz, 1H), 3.50 (d, J=13.6 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −112.95; IR (Thin Film) 3217, 1411, 1092, 1007, 725 cm⁻¹; HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₇H₁₄BrFN₃O, 374.0299; found, 374.0299.

Step B: Preparation of 2-(3-fluorophenyl)-1-(pyrimidin-5-yl)-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)ethanol

The title compound was prepared from 1-(5-bromopyridin-2-yl)-2-(3-fluorophenyl)-1-(pyrimidin-5-yl)ethanol and (4-(trifluoromethoxy)phenyl)boronic acid according to the conditions described in Example 7A and was isolated as a light-yellow, viscous, semi-solid in 64% yield: See Table 2 for characterization data.

Example 21: Preparation of 1-(5-(4-(1,1-difluoroethyl)phenyl)pyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol (55)

Step A: Preparation of 1-bromo-4-(1,1-difluoroethyl)benzene

To a vial equipped with a magnetic stir bar were added a solution of 1-(4-bromophenyl)ethanone (295 mg, 1.48 mmol) in anhydrous DCM (3.0 mL) followed by a 50% solution of Deoxofluor® in toluene (1.6 mL, 4.45 mmol) at room temperature under N₂ and the vial was sealed. The reaction mixture was stirred for approximately 15 h at room temperature, but little conversion had taken place. The mixture was concentrated, treated with additional Deoxofluor® solution (0.66 mL, 1.79 mmol), and warmed to and stirred at 85° C. under N₂ for 5 h. The reaction mixture was cooled to 0° C. and carefully quenched by adding sat'd aq NaHCO₃ dropwise until gas evolution ceased. The bi-phasic mixture was extracted with DCM (2×5 mL), and the combined extracts were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→50% EtOAc in hexanes) to afford the title compound (83 mg, 25%) as a clear liquid: ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.53 (m, 2H), 7.41-7.35 (m, 2H), 1.90 (t, J=18.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −87.86; IR (Thin Film) 1599, 1294, 1089 cm⁻¹; EIMS m/z 220/221.

Step B: Preparation of 2-(4-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared from 1-bromo-4-(1,1-difluoroethyl)benzene according to the conditions described in Example 17A and was isolated as a brown oil and used without further purification: ¹H NMR (400 MHz, CDCl₃) δ 7.91-7.83 (m, 2H), 7.55-7.45 (m, 2H), 1.91 (t, J=18.2 Hz, 3H), 1.35 (s, 12H); ¹⁹F NMR (376 MHz, CDCl₃) δ −88.45; EIMS m/z 268.

Step C: Preparation of 1-(5-(4-(1,1-difluoroethyl)phenyl)pyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol

The title compound was prepared from 1-(5-bromopyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol and 2-(4-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane according to the conditions described in Example 7A and was isolated as a light brown solid in 65% yield: See Table 2 for characterization data.

Example 22: Preparation of 1-(5-(4-iodophenyl)pyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol (165)

To a vial equipped with a magnetic stir bar were added a solution of 2,2-dimethyl-1-(pyrimidin-5-yl)-1-(5-(4-(trimethylsilyl)phenyl)pyridin-2-yl)propan-1-ol (59 mg, 0.15 mmol) in DCM (753 μL) followed by a solution of ICl (48.9 mg, 0.301 mmol) in DCM (0.5 mL) and the reaction mixture was stirred at room temperature. After approximately 23 h, the mixture was treated with additional ICl solution (48.9 mg, 0.301 mmol) in DCM (0.5 mL), stirred for 4 h, and quenched with sat'd aq sodium thiosulfate (Na₂S₂O₃; 2 mL). The mixture was diluted with DCM (2 mL) and the phases were separated. The organic phase was washed with water (3×2 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, 0→50% EtOAc in hexanes) to afford the title compound (32 mg, 47%) as an off-white solid: See Table 2 for characterization data.

Example 23: Preparation of 5-(1-methoxy-2,2-dimethyl-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propyl)pyrimidine (277)

To a vial equipped with a magnetic stir bar was added 2,2-dimethyl-1-(pyrimidin-5-yl)-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-1-ol (27) (150 mg, 0.372 mmol) and dry THF (2479 μl), and the head space was purged with N₂. To this was added sodium hydride (29.7 mg, 0.744 mmol). The reaction mixture was stirred at 0° C. for 5 min at which point methyl iodide (58.1 μl, 0.930 mmol) was added via syringe. The reaction gradually warmed to rt and then was quenched after 16 h by the addition of 1.5 mL sat. aq. NH₄Cl. The reaction mixture was diluted with water and extracted 3× with EtOAc. The combined organic layers were dried by passing through a phase separator and volatiles were removed under N₂. The residue was purified by column chromatography (SiO₂, 0→25% EtOAc in hexanes) to give the title compound (128 mg, 82%) as an oily yellow solid: See Table 2 for characterization data.

Example 24: Preparation of 1-(5-(4-iodophenyl)pyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol (156)

Step A: Preparation of 2-(4-bromo-3-methylphenyl)-2-methylpropanenitrile

To a magnetically stirred mixture of 2-(4-bromo-3-methylphenyl)acetonitrile (1 g, 4.76 mmol) in dry THF (9.52 ml) at ice-bath temperatures was added NaH (0.571 g, 14.28 mmol) in a dry 100 mL round-bottomed flask under an argon atmosphere. The reaction mixture was stirred at ice-bath temperatures for 1 h, then iodomethane (0.893 ml, 14.28 mmol) was added dropwise and stirring was continued for 3 h. The reaction mixture was poured into crushed ice and water and extracted with ethyl acetate (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to afford 1.1 g (92%) of the title compound as a brown oil, which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=8.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.13 (dd, J=8.3, 2.5 Hz, 1H), 2.43 (s, 3H), 1.70 (s, 6H). GCMS m/z 237.

Step B: Preparation of 5-(2,2-dimethyl-1-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propyl)pyrimidine

In a 4-neck 500 mL flask equipped with condensor, stir bar, temperature probe, and nitrogen inlet, 1-(5-bromopyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol (9.74 g, 28.7 mmol) was stirred in dioxane (115 ml). Potassium acetate (3.70 g, 37.3 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (9.58 g, 37.3 mmol) were added. The mixture was sparged with nitrogen for 5 minutes. Pd(dppf)Cl₂ (1.070 g, 1.436 mmol) was added. The mixture was heated to 85° C. for 2 h, then was allowed to cool. The reaction mixture was diluted with DCM (100 mL) and filtered through Celite. The filtrate was concentrated to dryness to provide a gummy solid. The solid was slurried in MTBE (30 mL) and heptane (100 mL). A solid was collected, washed with heptane and vacuum-dried at 35° C. to afford 13.6 g (86%) of the title compound as a gray solid, which was used as-is without further purification. ¹H NMR (500 MHz, CDCl₃) δ 9.11 (s, 2H), 9.05 (s, 1H), 8.90 (s, 1H), 8.45 (dd, J=8.1, 1.4 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 1.43-1.23 (m, 24H), 1.02 (s, 9H).

Step C: Preparation of 2-(4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)-3-methylphenyl)-2-methylpropanenitrile

To a magnetically stirred mixture of 5-(2,2-dimethyl-1-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propyl)pyrimidine (400 mg, 0.808 mmol) in toluene (2.423 mL) was added 2-(4-bromo-3-methylphenyl)-2-methylpropanenitrile (385 mg, 1.615 mmol), cesium fluoride (368 mg, 2.423 mmol), and tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.121 mmol) in a dry 5 mL microwave vial under a N₂ atmosphere. Ethanol (0.808 mL) and water (0.808 mL) were added, and the reaction mixture was purged with argon for minute, then stirred at 110° C. for 30 minutes in the Biotage Initiator microwave. The reaction mixture was cooled to RT, diluted with DCM and sat'd aq. NH4Cl, and the entire mixture was filtered through a plug of cotton. The biphasic mixture was then separated on a phase sepator and the organic extracts were evaporated. The crude material was purified on silica (ISCO, 24 gram column, gradient from 10% to 50% EA/Hex over min) to afford partially purified product (254 mg). The material was triturated with benzene, then with petroleum ether to give a solid, which was washed with petroleum ether, but unable to be sufficiently purified away from a minor component. The mixture was repurified on silica (ISCO, 24 gram column, 30% isocratic EA/Hex) to afford 162 mg (48%) of the title compound as a white foam. See Table 2 for characterization data.

Example 25: 5-(2-cyanopropan-2-yl)-2-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)benzonitrile (175)

Step A: Preparation of 2-bromo-5-(hydroxymethyl)benzonitrile

To a magnetically stirred mixture of 2-bromo-5-formylbenzonitrile (1 g, 4.76 mmol) in dry EtOH (23.81 ml) at ice-bath temperatures was added NaBH₄ (0.216 g, 5.71 mmol) in a dry 100 mL round-bottomed flask under a N₂ atmosphere. The reaction mixture was stirred at reduced temperature and allowed to warm to rt overnight. The reaction mixture was evaporated to dryness, and the crude residue was diluted with sat'd aq. NH₄Cl and stirred for 30 minutes. Then, 2N HCl was added with continued stirring until bubbling ceased. The resulting white precipitate was filtered with suction and air-dried to afford 688 mg (65%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO) δ 7.84 (d, J=5.1 Hz, 1H), 7.83 (s, 1H), 7.61-7.57 (m, 1H), 5.57 (s, 1H), 4.51 (s, 2H). ¹³C NMR (101 MHz, DMSO) δ 143.50, 132.86, 132.85, 132.26, 122.08, 117.30, 113.98, 61.27. ESIMS m/z 212.0 [M+H]⁺.

Step B: Preparation of 2-bromo-5-(chloromethyl)benzonitrile

To a magnetically stirred mixture of 2-bromo-5-(hydroxymethyl)benzonitrile (0.5 g, 2.358 mmol) in dry DCM (11.79 ml) at ice-bath temperatures was added thionyl chloride (0.344 ml, 4.72 mmol) in a dry 50 mL round-bottomed flask. DMF (0.5 mL) was added to aid solubilization. The reaction mixture was stirred at reduced temperature for 15 min and then was allowed to warm to rt. After 1 h, GC-MS analysis indicated the reaction was complete. The reaction mixture was diluted with DCM and sat'd aq. NaHCO₃, then stirred vigorously for 30 min. The layers were separated, the aq layer was extracted again with DCM, and the combined DCM extracts were dried over sodium sulfate, and filtered through a phase separator. The DCM was evaporated to afford 485 mg (56%) of the title compound as a white wax. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J=3.8 Hz, 1H), 7.68 (d, J=2.1 Hz, 1H), 7.48 (dd, J=8.4, 2.3 Hz, 1H), 4.54 (s, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 137.70, 134.03, 133.82, 133.60, 125.14, 116.62, 116.36, 43.93. GC-MS m/z 231.

Step C: Preparation of 2-bromo-5-(cyanomethyl)benzonitrile

To a magnetically stirred mixture of 2-bromo-5-(chloromethyl)benzonitrile (0.485 g, 2.104 mmol) in dry DMSO (5.26 ml) was added sodium cyanide (0.155 g, 3.16 mmol) in a dry 25 mL vial under a N₂ atmosphere. The reaction mixture was stirred at rt overnight. GC-MS indicated the reaction was complete. The mixture was diluted with sat'd aq. NaHCO₃ and extracted with ether (3×). The combined ether extracts were dried over sodium sulfate, filtered, and evaporated. The crude material was purified on silica (ISCO, 40 gram column, gradient to 80% acetone/Hex over 20 min, monitor UV @ 220 nm) to afford 372 mg (72%) of the title compound as an orange wax. ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J=8.4 Hz, 1H), 7.64 (d, J=2.3 Hz, 1H), 7.46 (dd, J=8.3, 2.3 Hz, 1H), 3.78 (s, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 134.06, 133.48, 133.29, 130.30, 125.27, 116.90, 116.32, 23.00. GC-MS m/z 220.

Step D: Preparation of 2-bromo-5-(2-cyanopropan-2-yl)benzonitrile

To a magnetically stirred mixture of 2-bromo-5-(cyanomethyl)benzonitrile (0.372 g, 1.683 mmol) in dry THF (8.41 ml) at ice-bath temperatures was added NaH (0.202 g, 5.05 mmol) in a dry 50 mL round-bottomed flask under a N₂ atmosphere. The reaction mixture was stirred at reduced temperature for 5 min, then iodomethane (0.316 ml, 5.05 mmol) was added, and the reaction mixture was allowed to warm to rt overnight. The reaction mixture was diluted with ether and sat'd aq. NH₄Cl, and the layers were separated. The aq layer was extracted again with ether, and the combined ether extracts were dried over sodium sulfate, filtered through a short pad of silica, and evaporated to afford 419 mg (95%) of the title compound as a yellow wax. ¹H NMR (400 MHz, CDCl₃) δ 7.74 (s, 1H), 7.73 (d, J=6.0 Hz, 1H), 7.60 (dd, J=8.5, 2.5 Hz, 1H), 1.74 (s, 6H). 13C NMR (101 MHz, CDCl₃) δ 141.88, 133.86, 130.99, 130.88, 124.86, 122.87, 116.69, 116.60, 36.85, 28.82. GCMS m/z 248.

Step E: Preparation of 5-(2-cyanopropan-2-yl)-2-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)benzonitrile

To a magnetically stirred mixture of 5-(2,2-dimethyl-1-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propyl)pyrimidine (0.5 g, 1.010 mmol) in dry toluene (4.45 ml) and ethanol (0.297 ml) was added potassium phosphate (0.643 g, 3.03 mmol), 2-bromo-5-(2-cyanopropan-2-yl)benzonitrile (0.377 g, 1.514 mmol), tetrakis(triphenylphosphine)palladium(0) (0.117 g, 0.101 mmol), and water (0.297 ml) in a dry 10 mL microwave vial under an argon atmosphere. The reaction mixture was purged with argon for 1 min, then heated with stirring in the Biotage Initiator microwave at 110° C. for 30 min. The crude material was purified on silica (ISCO, gram column, gradient to 50% ether/DCM over 15 min) to afford 214 mg (49%) of the title compound as a white foam. ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 2H), 9.10 (s, 1H), 8.75 (d, J=1.6 Hz, 1H), 8.02 (dd, J=8.3, 2.3 Hz, 1H), 7.95-7.91 (m, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.86 (dd, J=8.3, 2.1 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 5.81 (s, 1H), 1.80 (s, 6H), 1.10 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 161.16, 157.01, 156.41, 146.60, 142.76, 140.39, 136.75, 136.73, 132.24, 130.71, 130.63, 130.44, 123.12, 122.12, 122.08, 117.50, 112.30, 40.25, 36.95, 28.90, 26.30. ESIMS m/z 412.5 [M+H]⁺.

Example 26: Preparation of 2-(4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)-3-(methylthio)phenyl)-2-methylpropanenitrile (216)

Step A: Preparation of 2-(3-fluoro-4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)phenyl)-2-methylpropanenitrile

The title compound (159) was prepared from 5-(2,2-dimethyl-1-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propyl)pyrimidine and 2-(4-bromo-3-fluorophenyl)-2-methylpropanenitrile according to the conditions described in Example 24C and was isolated in 43% as a brown oil. See Table 2 for characterization data.

Step B: Preparation of 2-(4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)-3-(methylthio)phenyl)-2-methylpropanenitrile

To a magnetically stirred mixture of 2-(3-fluoro-4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)phenyl)-2-methylpropanenitrile (50 mg, 0.124 mmol) in dry DMSO (1.648 mL) was added sodium thiomethoxide (43.3 mg, 0.618 mmol) in a dry 5 mL microwave vial under a N₂ atmosphere. The reaction mixture was stirred at 100° C. in the microwave for 45 min, then overnight at rt. UPLC-MS analysis indicated ˜75% conversion. The reaction mixture was resubjected to heating in the microwave for 30 min at 100° C. The reaction mixture was cooled to rt and loaded directly onto silica. The crude material was purified on silica (ISCO, 24 gram column, stepwise gradient from 0% to 10% to 20% etc. to 60% ether/hexanes over 20 min) to afford only partially purified material. The product-containing fractions were combined and evaporated and the material was again purified on silica (ISCO, 24 gram column, gradient from 0 to 50% ether/DCM) to afford 45 mg (76%) of the title compound as a white foam. ¹H NMR (300 MHz, CDCl₃) δ 9.23 (s, 2H), 9.09 (s, 1H), 8.59 (dd, J=2.0, 1.0 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.84 (d, J=1.0 Hz, 1H), 7.44 (d, J=1.9 Hz, 1H), 7.31 (dd, J=8.0, 2.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 6.30 (s, 1H), 2.42 (s, 3H), 1.79 (s, 6H), 1.09 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 159.25, 158.68, 156.90, 156.43, 147.21, 142.40, 138.62, 137.54, 137.11, 135.79, 134.67, 130.58, 124.07, 122.80, 121.73, 121.49, 40.14, 37.26, 29.11, 26.35, 15.97. ESIMS m/z 433.5 [M+H]⁺.

Example 27: Preparation of 1-(pyrimidin-5-yl)-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)but-2-yn-1-ol (199)

Step A: Preparation of N-methoxy-N-methylpyrimidine-5-carboxamide

To a stirred mixture of pyrimidine-5-carboxylic acid (2.5 g, 20.15 mmol), and N,O-dimethyl hydroxylamine hydrochloride (2.49 g, 25.5 mmol) in DCM (50 mL), EDC.HCl (4.63 g, 24.17 mmol) and DMAP (3.69 g, 30.2 mmol) were added under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure; the obtained crude material was purified by flash column chromatography (100-200, SiO₂, 50-70% EA/Hexanes) to get N-methoxy-N-methylpyrimidine-5-carboxamide as a pale brown liquid. The product was confirmed by ¹H NMR and LCMS. (2.8 g, 83%). ¹H NMR (400 MHz, CDCl₃) δ 9.28 (s, 1H), 9.10 (s, 2H), 3.59 (s, 3H), 3.41 (s, 3H); ESIMS m/z 167.97 [M+H]⁺.

Step B: Preparation of (5-bromopyridin-2-yl)(pyrimidin-5-yl)methanone

To a stirred solution of 5-bromo-2-iodopyridine (5 g, 17.60 mmol) in dry THF (50 mL), was added isopropyl magnesium chloride (2.0 M, 9.7 mL, 19.36 mmol) at 0° C. and the reaction mixture was stirred for 15 min at 0° C. before the addition of N-methoxy-N-methylpyrazine-2-carboxamide (3.2 g, 19.36 mmol) in dry THF (10 mL). The resulting reaction mixture was stirred for 2 h at RT. Then the reaction mixture was quenched with saturated NH₄Cl solution and was extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and was concentrated under reduced pressure. The obtained crude product was purified by column chromatography (100-200 mesh silica) to afford (5-bromopyridin-2-yl) (pyrazin-2-yl) methanone (2) as a pale yellow solid (2 g, 43%). ¹H NMR (300 MHz, CDCl₃) δ 9.49 (s, 2H), 9.38 (s, 1H), 8.82 (s, 1H), 8.12 (d, J=2.1 Hz, 2H); ESIMS m/z 264.10 [M+H]⁺.

Step C: Preparation of pyrimidin-5-yl(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methanone

To a stirred solution of 5-bromopyridin-2-yl)(pyrimidin-5-yl)methanone (1.0 g, 3.816 mmol) in dry THF (25 mL) was added 4-(trifluoromethoxy)phenylboronic acid (0.930 g, 4.580 mmol) and K₃PO₄ (2.57 g, 11.450 mmol). The reaction mixture was then degassed with argon for 5 min, X-phos (70 mg, 4 mol %) and Pd(OAc)₂ (50 mg, 2 mol %) were added, and the reaction mixture was heated to 70-80° C. in a closed vessel for 5 h. The reaction mixture was cooled to room temperature, diluted with water and was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried over anhydrous MgSO₄ and the volatiles were removed under reduced pressure. The resulting crude material was purified by column chromatography, eluting with 20-25% ethyl acetate in hexanes to afford pyrimidin-5-yl(5-(4-(trifluoromethoxy) phenyl)pyridin-2-yl)methanone (3) as a pale yellow solid (1.0 g, 63%); ¹H NMR (400 MHz, CDCl₃) δ 9.55 (s, 2H), 9.39 (s, 1H), 8.84 (d, J=1.5 Hz, 1H), 8.33 (dd, J=2.4, 8.0 Hz, 1H), 8.16 (dd, J=2.4, 8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H); ESIMS m/z 346.47[M+H]⁺.

Step D: Preparation of 1-(pyrimidin-5-yl)-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)but-2-yn-1-ol

A stirred solution of pyrimidin-5-yl(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methanone (0.505 g, 1.464 mmol) in dry THF (17 mL) was cooled to −78° C., Prop-1-yn-1-ylmagnesium bromide (0.5 M, 8.78 mL, 4.39 mmol) was added and stirred for 1 h at −78° C. The reaction mixture was quenched with saturated aq. NH4Cl solution and was extracted with Ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica) to afford 350 mg (62%) of the title compound as a brown sticky liquid. See Table 2 for characterization data.

Example 28: Preparation of 2-(4-(6-(1-hydroxy-1-(4-methoxypyrimidin-5-yl)-2,2-dimethylpropyl)pyridin-3-yl)-3-methylphenyl)-2-methylpropanenitrile (129)

Step A: Preparation of N,4-dimethoxy-N-methylpyrimidine-5-carboxamide

In a 500 mL single-neck flask equipped with a stir bar, 4-methoxypyrimidine-5-carboxylic acid (8.0 g, 33.2 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.30 g, 43.2 mmol) were stirred in DCM (166 ml). DMAP (6.15 g, 49.8 mmol) and EDC hydrochloride (7.72 g, 39.9 mmol) were added. The mixture was stirred at 18° C. for 64 h, then silica (˜50 g) was added to the reaction mixture. The yellow suspension was concentrated then loaded onto silica (˜100 g). Chromatographed through a silica column (80 g) using EtOAc. The product fractions were concentrated to provide 2.4 g (36%) of the title compound a colorless oil which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 8.81 (s, 1H), 8.48 (s, 1H), 4.05 (d, J=0.7 Hz, 3H), 3.55 (s, 3H), 3.35 (s, 3H).

Step B: Preparation of (5-bromopyridin-2-yl)(4-methoxypyrimidin-5-yl)methanone

In a 3-neck 250 mL flask equipped with nitrogen inlet and temperature probe, 5-bromo-2-iodopyridine (5.02 g, 17.34 mmol) was stirred in THF (28.9 ml) at −15° C. Isopropylmagnesium chloride (2M, THF) (8.67 ml, 17.34 mmol) was added dropwise to maintain T<−10° C. The brown suspension was stirred for 1 h at −10° C. A solution of N,4-dimethoxy-N-methylpyrimidine-5-carboxamide (2.4 g, 11.56 mmol) in THF (20 mL) was added dropwise to maintain T=−10° C. After stirring at −10° C. for 30 min (solids dissolved), the cold bath was kept in place and the mixture was allowed to warm. After 3 h, the temperature had reached 5° C. 1N HCl (20 mL) was added to adjust the pH to ˜7. The mixture was extracted with EtOAc (2×100 mL). The combined extracts were dried over Na₂SO₄, filtered and concentrated to provide a yellow oil. The crude material was loaded onto silica (25 g) using DCM and chromatographed on silica (80 g) using 40% EtOAc/hexanes to afford 2.19 g (61%) of the title compound as beige solid. ¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J=1.7 Hz, 1H), 8.74-8.66 (m, 2H), 8.06 (dd, J=8.3, 2.1 Hz, 1H), 8.03-7.97 (m, 1H), 3.95 (d, J=1.7 Hz, 3H). HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₁H₉BrN₃O₂, 293.9873; found, 293.9873.

Step C: Preparation of 1-(5-bromopyridin-2-yl)-1-(4-methoxypyrimidin-5-yl)-2,2-dimethylpropan-1-ol

In a 200 mL single-neck flask equipped with stir bar, temperature probe and nitrogen inlet, (5-bromopyridin-2-yl)(4-methoxypyrimidin-5-yl)methanone (2.19 g, 7.07 mmol) was stirred in THF (60 mL). The solution was cooled to −75° C. Tert-Butylmagnesium chloride (2M, Et₂O) (4.24 mL, 8.49 mmol) was added dropwise by syringe maintaining T<−70° C. The orange mixture was stirred at −75° C. After 1 h, the cold bath was removed and the mixture was quickly but cautiously quenched with 0.5N HCl (17 mL) (final pH ˜7). The mixture was extracted with EtOAc (2×50 mL). The combined extracts were dried over Na₂SO₄, filtered and concentrated to provide an orange oil. The oil was dissolved in DCM and loaded onto silica (25 g). Purification via flash chromatography (silica, 25-40% EtOAc/Hexanes) afforded 1.38 g (50%) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 9.12 (s, 1H), 8.66 (s, 1H), 8.58 (dd, J=2.4, 0.5 Hz, 1H), 7.77 (dd, J=8.7, 2.4 Hz, 1H), 7.61 (dd, J=8.5, 0.6 Hz, 1H), 5.44 (s, 1H), 3.84 (s, 3H), 1.11 (s, 9H). HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₅H₁₉BrN₃O₂, 352.0655; found, 352.0649.

Step D: Preparation of 5-(2,2-dimethyl-1-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propyl)-4-methoxypyrimidine

In a single-neck 200 mL flask equipped with stir bar, temperature probe and nitrogen inlet, 1-(5-bromopyridin-2-yl)-1-(4-methoxypyrimidin-5-yl)-2,2-dimethylpropan-1-ol (1.38 g, 3.53 mmol) was stirred in dioxane (35.3 ml). Potassium acetate (0.454 g, 4.58 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.904 g, 3.53 mmol) were added. The mixture was sparged with nitrogen for 5 min. Pd(dppf)Cl₂ (0.131 g, 0.176 mmol) was added. The mixture was heated to 85° C. After 3 h, no starting material was detected by UPLC. The mixture was allowed to cool to rt. The mixture was diluted with DCM (50 mL) and filtered through Celite. The filtrate was concentrated to dryness to provide a black foam. The crude foam was taken up in DMSO (˜8 mL) and MeOH (˜3 mL) and was purified via reverse phase chromatography (C18, 250 g, 30-70% ACN/water) to afford 750 mg (36%) of title compound as a white solid which was used as-is without further purfication. ¹H NMR (400 MHz, CDCl₃) δ 9.27 (s, 1H), 8.85 (s, 1H), 8.65 (s, 1H), 8.33 (q, J=8.1 Hz, 2H), 3.85 (s, 3H), 1.44-0.84 (m, 33H).

Step E: Preparation of 2-(4-(6-(1-hydroxy-1-(4-methoxypyrimidin-5-yl)-2,2-dimethylpropyl)pyridin-3-yl)-3-methylphenyl)-2-methylpropanenitrile

To a magnetically stirred mixture of 5-(2,2-dimethyl-1-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propyl)-4-methoxypyrimidine (100 mg, 0.190 mmol) in dry toluene (2285 μl) was added 2-(4-bromo-3-methylphenyl)-2-methylpropanenitrile (54.4 mg, 0.228 mmol) (prepared as described in 24A), cesium fluoride (87 mg, 0.571 mmol), and tetrakis(triphenylphosphine)palladium (0) (22.00 mg, 0.019 mmol) in a dry 5 mL microwave vial under a N₂ atmosphere. EtOH (762 μl) and water (762 μl) were added, and the reaction mixture was purged with argon for 1 min. The reaction mixture was stirred at 110° C. for 30 min in a Biotage Initiator microwave, cooled to rt, and loaded onto a Celite dry-load cartridge. The crude material was purified on silica (ISCO, 24 gram column, gradient to 50% ether/DCM over 15 min) to afford 40 mg (46.4%) of the title compound as a clear viscous oil. See Table 2 for characterization data.

Example 29: Preparation of 2-(3-ethyl-4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)phenyl)-2-methylpropanenitrile (112)

Step A: Preparation of 4-bromo-3-ethylbenzaldehyde

To a 200 mL round bottom flask was added 1-bromo-2-ethyl-4-iodobenzene (5.0 g, 16.08 mmol) and ethyl ether (161 mL). The reaction was placed under inert atmosphere and cooled in a dry ice/acetone bath. Then n-butyllithium (6.75 mL, 16.88 mmol) was added dropwise. The reaction was allowed to stir for 20 min. Then N,N-dimethylformamide (1.364 mL, 17.69 mmol) was added and the reaction was allowed to warm to rt as the ice bath melted. The reaction mixture was poured into brine solution and extracted with EtOAc (2×25 mL). The combined organics were dried over MgSO₄, filtered, and concentrated. The resulting residue was purified by flash chromatography (ISCO 24 g silica 0-30% EtOAc in Hex) to afford 2.95 g (85%) of the title compound as a yellow liquid. ¹H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 7.86 (t, J=2.2 Hz, 1H), 7.82 (dd, J=8.2, 3.1 Hz, 1H), 7.66 (dt, J=8.2, 2.1 Hz, 1H), 2.79 (qd, J=7.5, 2.5 Hz, 2H), 1.22 (td, J=7.5, 1.7 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ 192.25, 143.66, 135.68, 133.36, 130.37, 130.18, 128.31, 28.50, 13.74. EIMS m/z 213.

Step B: Preparation of (4-bromo-3-ethylphenyl)methanol

To a 200 mL round bottom flask charged with 4-bromo-3-ethylbenzaldehyde (2.954 g, 13.86 mmol) was added THF (100 mL) and sodium borohydride (0.551 g, 14.56 mmol). The reaction was allowed to stir overnight at rt. The reaction was quenched with water. The resulting solution was poured into brine solution and extracted with EtOAc (3×50 mL). The combined organics were dried over MgSO₄ filtered and concentrated. The resulting residue was purified by flash chromatography (ISCO 40 g silica 0-20% EtOAc in Hex) to afford 2.58 g (86%) of the title compound as light yellow liquid. ¹H NMR (400 MHz, DMSO) δ 7.50 (d, J=8.2 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 7.08 (dd, J=8.2, 2.2 Hz, 1H), 5.25 (t, J=5.7 Hz, 1H), 4.46 (d, J=5.7 Hz, 2H), 2.69 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H). ¹³C NMR (126 MHz, DMSO) δ 142.97, 142.57, 132.49, 128.27, 126.43, 121.72, 62.67, 29.20, 14.77. EIMS m/z 215.

Step C: Preparation of 1-bromo-4-(chloromethyl)-2-ethylbenzene

To a 200 mL round bottom flask charged with (4-bromo-3-ethylphenyl)methanol (2.576 g, 11.98 mmol) was added dichloromethane (DCM) (100 mL), triethylamine (3.34 mL, 23.95 mmol), and methanesulfonyl chloride (1.120 mL, 14.37 mmol). The reaction was allowed to stir at room temperature for over the weekend. The reaction was poured into brine solution and extracted with additional DCM (3×30 mL). The combined organics were dried over MgSO4 filtered and concentrated. The resulting residue was purified by flash chromatography (ISCO 40 g Silica 0-50% EtOAc in Hex) to afford 1.9 g (67%) of the title compound as a clear liquid. ¹H NMR (400 MHz, DMSO) δ 7.57 (d, J=8.2 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.21 (dd, J=8.2, 2.3 Hz, 1H), 4.73 (s, 2H), 2.70 (q, J=7.5 Hz, 2H), 1.17 (t, J=7.5 Hz, 3H). ¹³C NMR (126 MHz, DMSO) δ 143.36, 138.00, 133.15, 130.59, 128.75, 123.77, 45.80, 29.12, 14.55. EIMS m/z 233.

Step D: Preparation of 2-(4-bromo-3-ethylphenyl)acetonitrile

To a 200 mL round bottom flask, charged with 1-bromo-4-(chloromethyl)-2-ethylbenzene (1.9 g, 8.14 mmol) was added DMF (40.7 ml) and potassium cyanide (0.583 g, 8.95 mmol). The reaction was allowed to stir for 3 h. Analysis by GCMS showed ˜50% completion. The reaction was allowed to stir overnight at rt. The reaction was poured into saturated Na₂CO₃ solution and extracted with EtOAc (3×40 mL). The combined organics were dried over MgSO₄ filtered and concentrated. The resulting residue was purified by flash chromatography (ISCO 40 g silica 0-40 EtOAc in Hex) to afford 1.152 g (63%) of the title compound as a clear liquid. ¹H NMR (400 MHz, DMSO) δ 7.60 (d, J=8.2 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.14 (dd, J=8.2, 2.4 Hz, 1H), 4.02 (s, 2H), 2.70 (q, J=7.5 Hz, 2H), 1.17 (t, J=7.5 Hz, 3H). ¹³C NMR (126 MHz, DMSO) δ 143.67, 133.39, 131.69, 129.98, 128.09, 123.02, 119.39, 29.13, 22.36, 14.58. EIMS m/z 224.

Step E: Preparation of 2-(4-bromo-3-ethylphenyl)-2-methylpropanenitrile

To a 20 mL vial charged with 2-(4-bromo-3-ethylphenyl)acetonitrile (1.052 g, 4.69 mmol) was added THF (45.0 mL). The reaction was cooled in a ice water bath, then potassium tert-butoxide (1.185 g, 10.56 mmol) was added. The reaction was allowed to stir for 20 min then iodomethane (0.646 mL, 10.33 mmol) was added. The reaction was allowed to stir for 4 h. The reaction was then poured into brine solution and extracted with EtOAc (2×30 mL). The combined organics were dried over MgSO₄, filtered and concentrated. The resulting residue was purified by flash chromatography (ISCO 40 g silica 0-30% EtOAc in Hex) to afford 1.05 g (88%) of the title compound as a semi-solid. ¹H NMR (300 MHz, DMSO) δ 7.62 (d, J=8.4 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.29 (dd, J=8.4, 2.6 Hz, 1H), 2.73 (q, J=7.5 Hz, 2H), 1.68 (s, 6H), 1.18 (t, J=7.5 Hz, 3H). ¹³C NMR (126 MHz, DMSO) δ 143.69, 141.88, 133.31, 127.21, 125.31, 124.79, 123.08, 36.89, 29.35, 28.64, 14.77. EIMS m/z 252.

Step F: Preparation of 2-(3-ethyl-4-(6-(1-hydroxy-2,2-dimethyl-1-(pyrimidin-5-yl)propyl)pyridin-3-yl)phenyl)-2-methylpropanenitrile

To a 20 mL microwave vessel 5-(2,2-dimethyl-1-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propyl)pyrimidine (500 mg, 1.010 mmol), potassium phosphate (536 mg, 2.52 mmol) and bis(triphenylphosphine)palladium(II) chloride (35.4 mg, 0.050 mmol) were charged. The vessel was sealed and pumped and purged with N₂ gas (3×). Then a solution of 2-(4-bromo-3-ethylphenyl)-2-methylpropanenitrile (305 mg, 1.212 mmol) in Dioxane (5.0 mL) was added followed by water (1.250 mL). The reaction was pumped and purged with N₂ gas (3×). The reaction was heated to 100° C. for 1 h using microwave power. The reaction was poured into brine solution and extracted with EtOAc (2×25 mL). The combined organics were dried over MgSO₄ filtered and concentrated. The resulting residue was purified by flash chromatography (ISCO 40 g silica 0-70% EtOAc in Hexanes) and reverse phase chromatography (ISCO 100 g C18 5-100% ACN in H₂O) to afford 225 mg (53%) of the title compound as a white foam. See Table 2 for characterization data.

Example 30: Preparation of 1-(4-methoxypyrimidin-5-yl)-2,2-dimethyl-1-(5-(2,2,2-trifluoroethoxy)-[2,3′-bipyridin]-6′-yl)propan-1-ol (119)

Step A: Preparation of N,4-dimethoxy-N-methylpyrimidine-5-carboxamide

In a 500 mL single-neck flask equipped with a stir bar 4-methoxypyrimidine-5-carboxylic acid (8.0 g, 33.2 mmol) and N, O-dimethylhydroxylamine hydrochloride (4.30 g, 43.2 mmol) were stirred in DCM (166 ml). DMAP (6.15 g, 49.8 mmol) and EDC hydrochloride (7.72 g, 39.9 mmol) were added. The mixture was stirred at 18° C. for 64 h, then silica (˜50 g) was added to the reaction mixture. The yellow suspension was concentrated then loaded onto silica (˜100 g). Chromatographed through a silica column (80 g) using EtOAc. The product fractions were concentrated to provide 2.4 g (36%) of the title compound a colorless oil which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 8.81 (s, 1H), 8.48 (s, 1H), 4.05 (d, J=0.7 Hz, 3H), 3.55 (s, 3H), 3.35 (s, 3H).

Step B: Preparation of (5-bromopyridin-2-yl)(4-methoxypyrimidin-5-yl)methanone

In a 3-neck 250 mL flask equipped with nitrogen inlet and temperature probe, 5-bromo-2-iodopyridine (5.02 g, 17.34 mmol) was stirred in THF (28.9 ml) at −15° C. Isopropylmagnesium chloride (2M, THF) (8.67 ml, 17.34 mmol) was added dropwise to maintain T<−10° C. The brown suspension was stirred for 1 h at −10° C. A solution of N,4-dimethoxy-N-methylpyrimidine-5-carboxamide (2.4 g, 11.56 mmol) in THF (20 mL) was added dropwise to maintain T=−10° C. After stirring at −10° C. for 30 min, the cold bath was kept in place and the mixture was allowed to warm. After 3 h, the temperature had reached 5° C. 1 N HCl (20 mL) was added to adjust the pH to ˜7. The mixture was extracted with EtOAc (2×100 mL). The combined extracts were dried over Na₂SO₄, filtered and concentrated to provide a yellow oil. The crude material was loaded onto silica (25 g) using DCM and chromatographed on silica (80 g) using 40% EtOAc/hexanes to afford 2.19 g (61%) of the title compound as beige solid. ¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J=1.7 Hz, 1H), 8.74-8.66 (m, 2H), 8.06 (dd, J=8.3, 2.1 Hz, 1H), 8.03-7.97 (m, 1H), 3.95 (d, J=1.7 Hz, 3H). HRMS-ESI (m/z) [M+H]⁺ calcd for Cl₁H₉BrN₃O₂, 293.9873; found, 293.9873.

Step C: Preparation of 1-(5-bromopyridin-2-yl)-1-(4-methoxypyrimidin-5-yl)-2,2-dimethylpropan-1-ol

In a 200 mL single-neck flask equipped with stir bar, temperature probe and nitrogen inlet, (5-bromopyridin-2-yl)(4-methoxypyrimidin-5-yl)methanone (2.19 g, 7.07 mmol) was stirred in THF (60 ml). The solution was cooled to −75° C. tert-Butylmagnesium chloride (2M, Et2O) (4.24 ml, 8.49 mmol) was added dropwise by syringe maintaining T<−70° C. The orange mixture was stirred at −75° C. After 1 h, the cold bath was removed and the mixture was quickly but cautiously quenched with 0.5 N HCl (17 mL). (final pH ˜7). The mixture was extracted with EtOAc (2×50 mL). The combined extracts were dried over Na₂SO₄, filtered and concentrated to provide an orange oil. The oil was dissolved in DCM and loaded onto silica (25 g). Purification via flash chromatography on silica (80 g) using 25-40% EtOAc/hexanes afforded 1.38 g (50%) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 9.12 (s, 1H), 8.66 (s, 1H), 8.58 (dd, J=2.4, 0.5 Hz, 1H), 7.77 (dd, J=8.7, 2.4 Hz, 1H), 7.61 (dd, J=8.5, 0.6 Hz, 1H), 5.44 (s, 1H), 3.84 (s, 3H), 1.11 (s, 9H). HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₅H₁₉BrN₃O₂, 352.0655; found, 352.0649.

Step D: Preparation of 5-(2,2-dimethyl-1-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propyl)-4-methoxypyrimidine

In a single-neck 200 mL flask equipped with stir bar, temperature probe and nitrogen inlet, 1-(5-bromopyridin-2-yl)-1-(4-methoxypyrimidin-5-yl)-2,2-dimethylpropan-1-ol (1.38 g, 3.53 mmol) was stirred in dioxane (35.3 ml). Potassium acetate (0.454 g, 4.58 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.904 g, 3.53 mmol) were added. The mixture was sparged with nitrogen for 5 min. Pd(dppf)Cl₂ (0.131 g, 0.176 mmol) was added. The mixture was heated to 85° C. After 3 h, no starting material was detected by UPLC. The mixture was allowed to cool. The mixture was diluted with DCM (50 mL) and filtered through Celite. The filtrate was concentrated to dryness to provide a black foam. The crude foam was taken up in DMSO (˜8 mL) and MeOH (˜3 mL) and chromatographed on C18 (250 g) using 30-70% ACN/water to afford 750 mg (36%) of title compound as a white solid which was used without further purfication. ¹H NMR (400 MHz, CDCl₃) δ 9.27 (s, 1H), 8.85 (s, 1H), 8.65 (s, 1H), 8.33 (q, J=8.1 Hz, 2H), 3.85 (s, 3H), 1.44-0.84 (m, 33H).

Step E: Preparation of 2-bromo-5-(2,2,2-trifluoroethoxy)pyridine

To a stirred solution of 6-bromopyridin-3-ol (1 g, 5.73 mmol) in acetone (20 ml) was added 2,2,2-trifluoroethyl triflouro methanesulfonate (2.01 g, 8.67 mmol) followed by K₂CO₃ (1.17 g, 8.67 mmol) at rt under an inert atmosphere. The reaction mixture was heated at 60° C. for 2 h. Then, the reaction mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (SiO₂, 100-200 mesh) using 30% EtOAc in petroleum ether as an eluent afford the title compound (0.8 g, 54%). ¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J=3.6 Hz, 1H), 7.43 (d, J=8.8, 1H), 7.20-7.15 (m, 1H) 4.39 (q, J=8.0 Hz, 2H); ESIMS m/z 256 [M+H]⁺.

Step F: Preparation of 1-(4-methoxypyrimidin-5-yl)-2,2-dimethyl-1-(5-(2,2,2-trifluoroethoxy)-[2,3′-bipyridin]-6′-yl)propan-1-ol (119)

To a degassed solution of 15-(2,2-dimethyl-1-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propyl)-4-methoxypyrimidine (0.43 g, 0.83 mmol), 2-bromo-5-(2,2,2-trifluoroethoxy)pyridine (0.169 g, 0.66 mmol) and sodium carbonate (0.28 g, 2.64 mmol) in dioxane (6 mL) and water (2 mL) was added PdCl₂(dppf) (0.054 g, 0.007 mmol) under a N₂ atmosphere. The reaction mixture was stirred at 85° C. for 16 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The rude product was purified by column chromatography using 20% EtOAc/petroleum ether as an eluent to afford the title compound as a brown oil (99 mg, 33%). See Table 2 for characterization data.

Biology Examples Example A: Evaluation of Fungicidal Activity: Leaf Blotch of Wheat (Mycosphaerella graminicola; Anamorph: Septoria tritici; Bayer Code SEPTTR)

For Type A assays, technical grades of the experimental fungicides in Table 4 below were dissolved in acetone, and then mixed with nine volumes of water containing 110 ppm Triton X-100. The fungicide solutions were applied onto wheat seedlings using an automated booth sprayer. For Type B assays, emulsifiable concentrate (EC) formulations of technical grades of the experimental fungicides in Table 4 below were prepared at 10% (w/v), and then mixed with 150 volumes of 0.1% Trycol 5941. These solutions were applied onto wheat seedlings using an automated track sprayer at 200 L/ha. All sprayed plants were allowed to air dry prior to further handling.

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50% mineral soil/50% soil-less Metro mix until the first leaf was fully emerged, with 7-10 seedlings per pot. Prior to or after application of experimental fungicides, plants were inoculated either with spores of a standard laboratory SEPTTR isolate (SI SEPTTR) or with spores from a SEPTTR field isolate collected from Wellsbourne, England in 2012 (FI SEPTTR). After inoculation the plants were kept for 3 days at 20° C. in 100% relative humidity (one day in a dark dew chamber followed by two days in a lighted dew chamber). Plants were then transferred to a 20° C. greenhouse for disease development. When disease symptoms were fully expressed on untreated plants, infection levels on treated plants were assessed on a scale of 0 to 100 percent disease severity. Percent disease control was calculated using the ratio of disease severity on treated plants relative to untreated plants. The results are shown below in Table 4.

TABLE 1 Structure and Preparation Method. Prepared According Compound to Number Structure Example 1

Example 1 2

Example 2 3

Example 3 4

Prepared according to Example 2 using 3-(4-chloro-2- fluorophenyl)propanoic acid in 2A 5

Prepared according to Example 2 using 2-bromo-5-((5- (trifluoromethyl)pyridin-2- yl)oxy)pyridine in 23 6

Prepared according to Example 3 using 4-chlorophenol in 38 7

Prepared according to Example 3 using 4-chlorophenol in 38 and cyclopropyl-magnesium bromide in 3C 8

Prepared according to Example 3 using 4- (trifluoromethoxy)phenol in 3B and cyclopropylmagnesium bromide in 3C 9

Prepared according to Example 3 using 4- (trifluoromethoxy)phenol in 3B 10

Prepared according to Example 3 using 4-6-chloropyridin-3-ol in 3B 11

Prepared according to Example 3 using 4-6-chloropyridin-3-ol in 3B and cyclopropylmagnesium bromide in 3C 12

Prepared according to Example 2 using 3-(4-chloro-2- fluorophenyl)propanoic acid in 3A and 2-bromo-5-((5-(trifluoro- methyl)-pyridin-2- yl)oxy)pyridine in 3B 13

Prepared according to Example 3 using 5-chloropyridin-2-ol in 3B 14

Prepared according to Example 3 using 5-chloropyridin-2-ol in 3B and cyclopropylmagnesium bromide in 3C 15

Prepared according to Example 2 using 3-(4-chloro)propanoic acid in 3A and 2-bromo-5-((5- (trifluoromethyp-pyridin-2- yl)oxy)pyridine in 3B 16

Prepared according to Example 3 using 4-hydroxybenzonitrile in 3B 17

Prepared according to Example 3 using cyclopropylmagnesium bromide in 3C 18

Prepared according to Example 3 using 4-hydroxybenzonitrile in 3B and cyclopropylmagnesium bromide in 3C 19

Example 4 20

Prepared according to Example 3 using 4-chlorophenol in 3B and allylmagnesium bromide in 3C 21

Example 5 22

Prepared according to Example 5 using pyrimidin-5-yl(5-(4- (trifluoromethoxy)- phenoxy)pyridin-2- yl)methanone 23

Prepared according to Example 4 using 2-cyclopropyl-N- methoxy-N-methylacetamide in 4A 24

Prepared according to Example 4 using N-methoxy-N- methylisobutyramide in 4A 25

Example 6 26

Example 7 27

Example 8 28

Example 9 29

Example 10 30

Example 10 31

Prepared according to Example 10 using pyrimidin-5-yl(5-(4- (trifluoromethoxy)- phenoxy)pyridin-2- yl)methanone (obtained from 4- (trifluoromethoxy)-phenol in 3B) 32

Prepared according to Example 10 using pyrimidin-5-yl(5-(4- (trifluoromethoxy)- phenoxy)pyridin-2- yl)methanone (obtained from 4- (trifluoromethoxy)-phenol in 3B) 33

Prepared according to Example 10 using pyrimidin-5-yl(5-(4- (trifluoromethyl)- phenoxy)pyridin-2- yl)methanone (from 3B) 34

Prepared according to Example 10 using pyrimidin-5-yl(5-(4- (trifluoromethyl)- phenoxy)pyridin-2- yl)methanone (from 3B) 35

Prepared according to Example 10 using (5-((6-chloropyridin-3- yl)oxy)pyridin-2-yl)(pyrimidin-5- yl)methanone (obtained from 6- chloropyridin-3-ol in 3B) 36

Prepared according to Example 10 using (5-((6-chloropyridin-3- yl)oxy)pyridin-2-yl)(pyrimidin-5- yl)methanone (obtained from 6- chloropyridin-3-ol in 3B) 37

Prepared according to Example 3 using 4-hydroxybenzonitrile in 3B and allylmagnesium bromide in 3C 38

Prepared according to Example 6 using iso-propylmagnesium chloride in 6D 39

Prepared according to Example 6 using cyclopropylmagnesium bromide in 6D 40

Prepared according to Example 10 using ethynylcyclopropane 41

Example 11 42

Example 12 43

Prepared according to Example 4 using N-methoxy-N- methylpivalamide in 4A and 4- chlorophenol in 4B 44

Prepared according to Example 3 using 4-chlorophenol in 3B and tert-butyllithium in 3C 45

Example 13 46

Example 14 47

Prepared according to Example 10 using ethynylcyclopropane and pyrimidin-5-yl(5-(4- (trifluoromethyl)-phenoxy)- pyridin-2-yl)methanone (from 3B) 48

Prepared according to Example 10 using ethynylcyclopropane and pyrimidin-5-yl(5-(4- (trifluoromethoxy)-phenoxy)- pyridin-2-yl)methanone (from 3B) 49

Prepared according to Example 10 using (5-((5-chloropyridin-2- yl)oxy)pyridin-2-yl)(pyrimidin-5- yl)methanone (obtained from 5- chloropyridin-2-ol via 3B) 50

Prepared according to Example 10 using (5-((5-methylpyridin-2- yl)oxy)pyridin-2-yl)(pyrimidin-5- yl)methanone (obtained from 5- methylpyridin-2-ol via 3B) 51

Prepared according to Example 6 using tert-butylmagnesium bromide in 6D 52

Prepared according to Example 6 using cyclohexylmagnesium bromide in 6D 53

Prepared according to Example 3 using 5-methylpyridin-2-ol in 3B 54

Prepared according to Example 10 using (5-((5-chloropyridin-2- yl)oxy)pyridin-2-yl)(pyrimidin-5- yl)methanone (obtained from 5- chloropyridin-2-ol via 3B) 55

Prepared according to Example 10 using (5-((5-methylpyridin-2- yl)oxy)pyridin-2-yl)(pyrimidin-5- yl)methanone (obtained from 5- methylpyridin-2-ol via 3B) 56

Prepared according to Example 6 using cyclopentylmagnesium bromide in 6D 57

Prepared according to Example 6 using tert-pentylmagnesium bromide in 6D 58

Prepared according to Example 3 using 5- (trifluoromethyl)pyridin-2-ol in 3B 59

Prepared according to Example 8 using 2-bromo-5-(4- (difluoromethoxy)phenyl)- pyridine in 8A 60

Prepared according to Example 8 using 2-bromo-5-(4- (difluoromethoxy)phenyl)- pyridine in 8A and cyclopropylmagnesium bromide in 8B 61

Prepared according to Example 7 using isobutyryl chloride in 7B 62

Prepared according to Example 7 using (6-(2,2,2- trifluoroethoxy)pyridin-3- yl)boronic acid in 7A and isobutyryl chloride in 7B 63

Prepared according to Example 8 using i-PrMgCl in 8B 64

Prepared according to Example 8 using 6-bromo-6′-(2,2,2- trifluoroethoxy)-3,3′-bipyridine in 8A and i-PrMgCl in 8B 65

Prepared according to Example 8 using 2-2-bromo-5-(4- chlorophenyl)pyridine in 8A 66

Prepared according to Example 8 using 2-2-bromo-5-(4- chlorophenyl)pyridine in 8A and cyclopropylmagnesium bromide in 8B 67

Prepared according to Example 3 using 5- (trifluoromethyl)pyridin-2-ol in 3B and cyclopropyl-magnesium bromide in 3C 68

Prepared according to Example 6 using (4- (difluoromethoxy)phenyl)boronic acid in 6C and tert- butylmagnesium bromide in 6D 69

Prepared according to Example 3 using 6-chloropyridin-2-ol in 3B 70

Prepared according to Example 10 using (5-((6-chloropyridin-2- yl)oxy)pyridin-2-yl)(pyrimidin-5- yl)methanone (obtained from 6- chloropyridin-2-ol via 3B) 71

Prepared according to Example 10 using (5-((6-chloropyridin-2- yl)oxy)pyridin-2-yl)(pyrimidin-5- yl)methanone (obtained from 6- chloropyridin-2-ol via 3B) 72

Prepared according to Example 3 using 6-chloropyridin-2-ol in 3B and cyclopropyl-magnesium bromide in 3C 73

Prepared according to Example 8 using cyclopropylmagnesium bromide in 8B 74

Prepared according to Example 6 using (4- (trifluoromethoxy)phenyl)boronic acid in 6C and tert- butylmagnesium bromide in 6D 75

Prepared according to Example 3 using N-methoxy-N- methylnicotinamide in 3A 76

Prepared according to Example 3 using N-methoxy-N- methylnicotinamide in 3A and cyclopropylmagnesium bromide in 3C 77

Prepared according to Example 3 using N-methoxy-N- methylnicotinamide in 3A and 5- chloropyridin-2-ol in 3B 78

Prepared according to Example 8 using N-methoxy-N- methylnicotinamide in 8A and cyclopropylmagnesium bromide in 8B 79

Prepared according to Example 3 using N-methoxy-N- methylnicotinamide in 3A, 5- chloropyridin-2-ol in 3B, and cyclopropylmagnesium bromide in 3C 80

Prepared according to Example 8 using N-methoxy-N- methylnicotinamide in 8A 81

Prepared according to Example 8 using N-methoxy-N- methylnicotinamide and 2- bromo-5-(4- (difluoromethoxy)phenyl)- pyridine in 8A and cyclopropylmagnesium bromide in 8B 82

Prepared according to Example 8 using N-methoxy-N- methylnicotinamide and 2- bromo-5-(4- (difluoromethoxy)phenyl)- pyridine in 8A 83

Prepared according to Example 8 using N-methoxy-N,2- dimethylpyrimidine-5- carboxamide in 8A 84

Prepared according to Example 8 using N-methoxy-N- methylthiazole-5-carboxamide in 8A 85

Prepared according to Example 8 using N-methoxy-N- methylthiazole-5-carboxamide and 2-Bromo-5-(4- (difluoromethoxy)phenyl)- pyridine in 8A and i-PrMgCl in 8B 86

Prepared according to Example 8 using N-methoxy-N- methylthiazole-5-carboxamide and 2-Bromo-5-(4- (difluoromethoxy)phenyl)- pyridine in 8A 87

Prepared according to Example 8 using N-methoxy-N- methylthiazole-5-carboxamide in 8A and i-PrMgCl in 8B 88

Prepared according to Example 8 using 4-(6-bromopyridin-3- yl)benzonitrile in 8A 89

Prepared according to Example 8 using N-methoxy-N- methylthiazole-5-carboxamide in 8A and cyclopropylmagnesium bromide in 8B 90

Prepared according to Example 8 using (4-chloro-2- fluorobenzyl)magnesium bromide in 88 91

Example 15 92

Prepared according to Example 8 using 6-bromo-6′-(2,2,2- trifluoroethoxy)-3,3′-bipyridine in 8A 93

Example 16 94

Prepared according to Example 16A, 15, and 16C, using N-methoxy-N- methylthiazole-5-carboxamide (prepared from thiazole-5- carboxylic acid) in 16A and (4-(trifluoromethoxy)- phenyl)boronic acid in 16C 95

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-methoxyphenyl)boronic acid in 16C 96

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-(trifluoromethyl)- phenyl)boronic acid in 16C 97

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-(tert-butyl)phenyl)boronic acid in 16C 98

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-(methylthio)phenyl)boronic acid in 16C 99

Prepared according to Example 16A-16C, using methylmagnesium bromide in 16B and (4-(trifluoromethoxy)- phenyl)boronic acid in 16C 100

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-(dimethylamino)- phenyl)boronic acid in 16C 101

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-acetylphenyl)boronic acid in 16C 102

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-cyclopropoxyphenyl)boronic acid in 16C 103

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (3-(trifluoromethoxy)- phenyl)boronic acid in 16C 104

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (2-(trifluoromethoxy)- phenyl)boronic acid in 16C 105

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-(1-cyanocyclopropyl)- phenyl)boronic acid in 16C 106

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (3-fluoro-4-(trifluoromethoxy)- phenyl)boronic acid in 16C 107

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (6-(trifluoromethyppyridin-3- yl)boronic acid in 16C 108

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (6-cyanopyridin-3-yl)boronic acid in 16C 109

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-vinylphenyl)boronic acid in 16C 110

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and thiophen-3-ylboronic acid in 16C 111

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-(methoxymethyl)- phenyl)boronic acid in 16C 112

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (2-fluoropyridin-3-yl)boronic acid in 16C 113

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and pyrimidin-5-ylboronic acid in 16C 114

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and phenylboronic acid in 16C 115

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-fluorophenyl)boronic acid in 16C 116

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (3-methyl-4- (trifluoromethoxy)phenyl)- boronic acid in 16C 117

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (2-methyl-4- (trifluoromethoxy)phenyl)- boronic acid in 16C 118

Prepared according to Example 16A-16C, using N-methoxy-N,4- dimethylpyrimidine-5- carboxamide (prepared from 4- methylpyrimidine-5-carboxylic acid) in 16A, tert-butylmagnesium chloride in 16B, and (4-(trifluoromethoxy)- phenyl)boronic acid in 16C 119

Prepared according to Example 16A-16C, using 5-bromo-2-iodo-4-methyl- pyridine in 16A, tert-butylmagnesium chloride in 16B, and (4-(trifluoromethoxy)- phenyl)boronic acid in 16C 120

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-(2,2,2-trifluoroethoxy)- phenyl)boronic acid in 16C 121

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-(trimethylsilyl)- phenyl)boronic acid in 16C 122

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole in 16C 123

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and 2-(furan-3-yl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane in 16C 124

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and 2-(2-fluoro-4- (trifluoromethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (prepared from 1-bromo-2-fluoro-4- (trifluoromethoxy)benzene) in 16C 125

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and 4,4,5,5-tetramethy1-2-(4- ((trifluoromethyl)thio)phenyl)- 1,3,2-dioxaborolane in 16C 126

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and pyridin-3-ylboronic acid in 16C 127

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and quinolin-3-ylboronic acid in 16C 128

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (2,4-bis(trifluoromethyl)- phenyl)boronic acid in 16C 130

Example 18 131

Prepared according to Example 16A-16C, using 5-bromo-2-iodo-3-methyl- pyridine in 16A, tert-butylmagnesium chloride in 16B, and (4-(trifluoromethoxy)- phenyl)boronic acid in 16C 132

Example 18 133

Example 19 134

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and 4,4,5,5-tetramethyl-2- (thiophen-2-yl)-1,3,2- dioxaborolane in 16C 135

Prepared according to Example 20A-20B, using benzyl bromide in 20A 136

Prepared according to Example 20A -20B, using 4-fluorobenzyl bromide in 20A 137

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and 2-(chroman-6-yl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane in 16C 138

Prepared according to Example 20A-20B, using 2,4-difluorobenzyl bromide in 20A 139

Example 20 140

Prepared according to Example 20A-20B, using 4-chlorobenzyl bromide in 20A 141

Prepared according to Example 20A-20B, using 3-chlorobenzyl bromide in 20A 142

Prepared according to Example 20A-20B, using 2,4-dichlorobenzyl bromide in 20A 143

Prepared according to Example 16A-16C, using N-methoxy-N- methylnicotinamide (prepared from nicotinic acid) in 16A, tert-butylmagnesium chloride in 16B and 4-(tert-butylphenypboronic acid in 16C 144

Prepared according to Example 16A-16C, using N-methoxy-N,5- dimethylnicotinamide (prepared from 5-methylnicotinic acid) in 16A, tert-butylmagnesium chloride in 16B, and (4-(trifluoromethoxy)- phenyl)boronic acid in 16C 145

Prepared according to Example 16A-16C, using N-methoxy-N- methylnicotinamide (prepared from nicotinic acid) in 16A, tert-butylmagnesium chloride in 16B and 4-(1-cyanocyclopropyl)- phenyl)boronic acid in 16C 146

Prepared according to Example 16A-16C, using N-methoxy-N- methylnicotinamide (prepared from nicotinic acid) in 16A, tert-butylmagnesium chloride in 16B and 2-methyl-4-(trifluoromethoxy)- phenylboronic acid in 16C 147

Prepared according to Example 16A-16C, using N-methoxy-N- methylnicotinamide (prepared from nicotinic acid) in 16A, tert-butylmagnesium chloride in 16B and 2-(2-fluoro-4-(trifluoro- methoxy)phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (prepared from 1-bromo-2-fluoro-4- (trifluoromethoxy)-benzene) in 16C 148

Prepared according to Example 16A-16C, using N-methoxy-N,6- dimethylnicotinamide (prepared from 6-methylnicotinic acid) in 16A, tert-butylmagnesium chloride in 16B and 4-(trifluoromethoxy)- phenylboronic acid in 16C 149

Prepared according to Example 16A-16C, using N-methoxy-N,4- dimethylnicotinamide (prepared from 4-methylnicotinic acid) in 16A, tert-butylmagnesium chloride in 1613 and 4-(trifluoromethoxy)- phenylboronic acid in 16C 150

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and 4-methyl-2,6-dioxo-8-(5- (trifluoromethoxy)pyridin-2- yl)phexahydro-[1,3,2]oxaza- borolo[2,3-b][1,3,2]oxazaborol- 4-ium-8-uide in 16C 151

Prepared according to Example 16A-16C, using N-methoxy-N,2- dimethylnicotinamide (prepared from 2-methylnicotinic acid) in 16A, tert-butylmagnesium chloride in 16B and 4-(trifluoromethoxy)- phenylboronic acid in 16C 152

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-(2-cyanopropan-2- yl)phenyl)boronic acid in 16C 153

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-(cyanomethyl)phenyl)boronic acid in 16C 154

Prepared according to Example 16, using N-methoxy-N- methylnicotinamide (prepared from nicotinic acid) in 16A 155

Example 21 156

Prepared according to Example 16A-16C, using N-methoxy-N,4- dimethylpyrimidine-5- carboxamide (prepared from 4- methylpyrimidine-5-carboxylic acid) in 16A, tert-butylmagnesium chloride in 16B, and (2-methyl-4-(trifluoromethoxy)- phenyl)boronic acid in 16C 157

Prepared according to Example 16A-16C, using N-methoxy-N,4- dimethylpyrimidine-5- carboxamide (prepared from 4- methylpyrimidine-5-carboxylic acid) in 16A, tert-butylmagnesium chloride in 16B, and 2-(2-fluoro-4-(trifluoro- methoxy)phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane in 16C 158

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and 1-(3-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)cyclopropane- carbonitrile in 16C 159

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and 2-(4-cyclopropylphenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane in 16C 160

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and 4,4,5,5-tetramethyl-2-(4-(1- (trifluoromethyl)cyclopropyl)- phenyl)-1,3,2-dioxaborolane in 16C 161

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and 4,4,5,5-tetramethyl-2-(4- (perfluoroethoxy)phenyl)-1,3,2- dioxaborolane in 16C 162

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 1613 and (2-fluoro-4- methoxyphenyl)boronic acid in 16C 163

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (4-methoxy-2-(trifluoro- methoxy)phenyl)boronic acid in 16C 164

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (2,4-difluorophenyl)boronic acid in 16C 165

Example 22 166

Prepared according to Example 16A-16C, using tert-butylmagnesium chloride in 16B and (2-chloro-4-fluorophenyl)- boronic acid in 16C 167

Prepared according to Example 16A-16C, using N,4-dimethoxy-N- methylpyrimidine-5- carboxamide (prepared from 4-methoxypyrimidine-5- carboxylic acid) in 16A, tert-butylmagnesium chloride in 16B, and (4-(trifluoromethoxy)- phenyl)boronic acid in 16C 168

Prepared according to Example 16A-16C, using N,4-dimethoxy-N- methylpyrimidine-5- carboxamide (prepared from 4-methoxypyrimidine-5- carboxylic acid) in 16A, tert-butylmagnesium chloride in 16B, and (4-(tert-butyl)phenyl)boronic acid in 16C 169

Prepared according to Example 16A-16C, using N,4-dimethoxy-N- methylpyrimidine-5- carboxamide (prepared from 4-methoxypyrimidine-5- carboxylic acid) in 16A, tert-butylmagnesium chloride in 16B, and (4-(1-cyanocyclopropyl)- phenyl)boronic acid in 16C 170

Prepared according to Example 16A-16C, using N,4-dimethoxy-N- methylpyrimidine-5- carboxamide (prepared from 4-methoxypyrimidine-5- carboxylic acid) in 16A, tert-butylmagnesium chloride in 16B, and (4-cyanophenyl)boronic acid in 16C 171

Prepared according to Example 16A-16C, using N,4-dimethoxy-N- methylpyrimidine-5- carboxamide (prepared from 4-methoxypyrimidine-5- carboxylic acid) in 16A, tert-butylmagnesium chloride in 16B, and (6-methoxypyridin-3-yl)boronic acid in 16C 172

Prepared according to Example 16A-16C, using N,4-dimethoxy-N- methylpyrimidine-5- carboxamide (prepared from 4-methoxypyrimidine-5- carboxylic acid) in 16A, tert-butylmagnesium chloride in 16B, and (6-(trifluoromethyl)pyridin-3- yl)boronic acid in 16C 173

Prepared according to Example 23 from 2,2-dimethyl-1- (pyrimidin-5-yl)-1-(5- (trifluoromethoxy)-[2,3′- bipyridin]-6′-yl)propan-1-ol 174

Prepared according to Example 16 using N-methoxy-N- methylpyrazine-2-carboxamide in 16A, tert-butylmagnesium chloride in 1613, and 2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)-5- (trifluoromethoxy)pyridine (prepared as described in 17A from 2-bromo-5- (trifluoromethoxy)pyridine) in 16C 175

Example 25 176

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-2-methyl-1-(pyrimidin-5- yl)propan-1-ol (163) and iodoethane 177

Prepared according to Example 23 from 1-(pyrimidin-5-yl)-1-(5- (4-(trifluoromethoxy)phenyl)pyridin- 2-yl)ethanol and iodoethane 178

Prepared according to Example 6 using (4-(1- cyanocyclopropyl)phenyl)boronic acid in step 6C and tert- butylmagnesium chloride in step 6D. 179

Example 29 180

Prepared according to Example 16 using N-methoxy-N- methylpyrazine-2-carboxamide in 16A, tert-butylmagnesium chloride in 16B, and (6-(2,2,2- trifluoroethoxy)pyridin-3- yl)boronic acid in 16C 181

Prepared according to Example 6 using (4-(tert- butyl)phenyl)boronic acid in step 6C and tert- butylmagnesium chloride in step 6D. 182

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)but-2- yn-1-ol (118) and iodomethane 183

Prepared according to Example 25 using 2-(6-bromopyridin-3- yl)-2-methylpropanenitrile in 25E. 2-(6-bromopyridin-3-yl)-2- methylpropanenitrile was prepared from 6- bromonicotinaldehyde according to conditions described for 25A-25D 184

Prepared according to Example 27 using 2-(2-fluoro-4- (trifluoromethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (prepared as described in 17A) in 27C and cyclopropyl magnesium bromide in 27D 185

Prepared according to Example 27 using 2-(2-fluoro-4- (trifluoromethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (prepared as described in 17A) in 27C 186

Prepared according to Example 30 using 2-bromo-5-(2,2,2- trifluoroethoxy)pyridine in step 30F. 187

Prepared according to Example 28 using (2-fluoro-4- (trifluoromethoxy)phenyl)boronic acid in step 28F (skip steps 28D-E) 188

Prepared according to Example 16 using N-methoxy-N- methylpyrazine-2-carboxamide in 16A, tert-butylmagnesium chloride in 16B, and (4-(2- cyanopropan-2- yl)phenyl)boronic acid in 16C 189

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-2,2-dimethyl-1- (pyrimidin-5-yl)propan-1-ol and propargyl bromide 190

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)propan- 1-ol (138) and iodoethane 191

Prepared according to Example 23 from 2-methyl-1-(pyrimidin- 5-yl)-1-(5-(4- (trifluoromethoxy)phenyl)pyridin- 2-yl)propan-1-ol and propargyl bromide 192

Prepared according to Example 23 from 1-(4-(6-(1-hydroxy-2,2- dimethyl-1-(pyrimidin-5- yl)propyl)pyridin-3- yl)phenyl)cyclopropane- carbonitrile 193

Prepared according to Example 23 from cyclopropyl(pyrimidin- 5-yl)5-(4- (trifluoromethoxy)phenyl)pyridin- 2-yl)methanol 194

Prepared according to Example 23 from 2-methyl-1-(pyrimidin- 5-yl)-1-(5-(4- (trifluoromethoxy)phenyl)pyridin- 2-yl)propan-1-ol 195

Prepared according to Example 6 using 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2- (2,2,2-trifluoroethoxy)pyridine in step 6C and tert- butylmagnesium chloride in step 6D. 196

Example 28 197

Prepared according to Example 23 using propargyl bromide 198

Prepared according to Example 23 using iodoethane 199

Prepared according to Example 28 using 2-bromo-5- (trifluoromethoxy)pyridine in step 28E 200

Prepared according to Example 23 from cyclopropyl(5-(2-fluoro- 4- (trifluoromethoxy)phenyl)pyridin- 2-yl)(pyrimidin-5-yl)methanol (117) and iodomethane 201

Prepared according to Example 6 using nicotinaldehyde in step 6B, (4-(tert-butyl)phenyl)boronic acid in step 6C and tert- butylmagnesium chloride in step 6D. 202

Prepared according to Example 16 from 1-(5-bromopyridin-2- yl)-1-(5-fluoropyridin-3-yl)-2,2- dimethylpropan-1-ol (178) and (4-(trifluoromethoxy)phenyl) boronic acid in 16C. 203

Prepared according to Example 28 using (4-(2,2,2- trifluoroethoxy)phenyl)boronic acid in step 28F (skip steps 28D- E) 204

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)but-2- yn-1-ol (118) and iodoethane 205

Prepared according to Example 27 using 2-(2-fluoro-4- (trifluoromethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (prepared as described in 17A) in 27C and ethyl magnesium bromide in 27D 206

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)ethanol (154) and iodomethane 207

Prepared according to Example 16 using N-methoxy-N- methylpyrazine-2-carboxamide in 16A and tert-butylmagnesium chloride in 16B 208

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-2-methyl-1-(pyrimidin-5- yl)propan-1-ol (163) and propargyl bromide 210

Prepared according to Example 24 using 2-bromo-1,3-difluoro- 5-(trifluoromethoxy)benzene in 24C 211

Prepared according to Example 23 from 2,2-dimethyl-1-(5-(2- fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)propan- 1-ol 212

Prepared according to Example 24 using 1-(4-bromo-3- methylphenyl)cyclobutanecarbonitrile in 24C 213

Prepared according to Example 23 from 1-(pyrimidin-5-yl)-1-(5- (4- (trifluoromethoxy)phenyl)pyridin-2- yl)propan-1-ol (191) and iodomethane 214

Prepared according to Example 23 from 2-(4-(6-(1-methoxy-2,2- dimethyl-1-(pyrimidin-5- yl)propyl)pyridin-3-yl)phenyl)-2- methylpropanenitrile 215

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)ethanol (154) and iodoethane 216

Example 26 217

Prepared according to Example 23 from 1-(pyrimidin-5-yl)-1-(5- (4- (trifluoromethoxy)phenyl)pyridin- 2-yl)but-2-yn-1-ol (199) 218

Prepared according to Example 28 using 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2- (2,2,2-trifluoroethoxy)pyridine in step 28F (skip steps 28D-E) 219

Prepared according to Example 6 using (4- ((trifluoromethyl)thio)phenyl) boronic acid in step 6C and tert- butylmagnesium chloride in step 6D. 220

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-2,2-dimethyl-1- (pyrimidin-5-yl)propan-1-ol and iodoethane 221

Prepared according to Example 27 using 2-(2-fluoro-4- (trifluoromethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (prepared as described in 17A) in 27C and 27D methyl magnesium bromide in 27D 222

Prepared according to Example 28 using (2-methyl-4- (trifluoromethoxy)phenyl)boronic acid in step 28F (skip steps 28D-E) 223

Example 24 224

Prepared according to Example 16 using N-methoxy-N- methylpyrazine-2-carboxamide in 16A, tert-butylmagnesium chloride in 16B, and (2-methyl-4- (trifluoromethoxy)phenyl)boronic acid in 16C 225

Prepared according to Example 16 using N-methoxy-N- methylpyrazine-2-carboxamide in 16A, tert-butylmagnesium chloride in 16B, and (4-(2,2,2- trifluoroethoxy)phenyl)boronic acid in 16C 226

Prepared according to Example 24 using 2-(4-bromo-3-fluorophenyl)-2- methylpropanenitrile. 2-(4- bromo-3-fluorophenyl)-2- methylpropanenitrile was prepared from 2-(4-bromo-3- fluorophenyl)acetonitrile and iodomethane according to conditions described in 24A in 24C 227

Prepared according to Example 6 using nicotinaldehyde in step 6B, (4-(1- cyanocyclopropyl)phenyl)boronic acid in step 6C and tert- butylmagnesium chloride in step 6D. 228

Prepared according to Example 23 from 2-(3-fluoro-4-(6-(1- hydroxy-2,2-dimethyl-1- (pyrimidin-5-yl)propyl)pyridin-3- yl)phenyl)-2- methylpropanenitrile (159) 229

Prepared according to Example 16 using N-methoxy-N- methylpyrazine-2-carboxamide in 16A, tert-butylmagnesium chloride in 16B, and (4-(1- cyanocyclopropyl)phenyl) boronic acid in 16C 230

Prepared according to Example 27 using 2-(2-fluoro-4- (trifluoromethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (prepared as described in 17A) in 27C and isopropyl magnesium chloride in 27D 231

Prepared according to Example 6 using nicotinaldehyde in step 6B, (4- ((trifluoromethyl)thio)phenyl)boronic acid in step 6C and tert- butylmagnesium chloride in step 6D. 232

Prepared according to Example 23 from cyclopropyl(pyrimidin- (trifluoromethoxy)phenyl)pyridin- 2-yl)methanol and iodoethane 233

Prepared according to Example 28 using 1-(4-bromo-3- fluorophenyl)cyclopropane- carbonitrile in 28E 234

Prepared according to Example 6 using nicotinaldehyde in step 6B, 5-(4,4,5,5-tetramethy1-1,3,2- dioxaborolan-2-yl)-2-(2,2,2- trifluoroethoxy)pyridine in step 6C and tert-butylmagnesium chloride in step 6D. 235

Prepared according to Example 16 using 2-chloro-N-methoxy-N- methylnicotinamide in 16A and tert-butylmagnesium chloride in 16B 236

Prepared according to Example 24 using 1-(4-bromo-3- fluorophenyl)cyclopropane- carbonitrile in 24C 237

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)ethanol (154) and propargyl bromide 238

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)propan- 1-ol (138) and propargyl bromide 239

Prepared according to Example 29 using 2-(6-bromo-5- methylpyridin-3-yl)-2- methylpropanenitrile in 29F. 2- (6-bromo-5-methylpyridin-3-yl)- 2-methylpropanenitrile was prepared from 6-bromo-5- methylnicotinaldehyde according to conditions described for 29B-29E 240

Prepared according to Example 28 using 2-(4-bromophenyl)-2- methylpropanenitrile in 28E 241

Prepared according to Example 23 from 1-(pyrimidin-5-yl)-1-(5- (4- (trifluoromethoxy)phenyl)pyridin- 2-yl)ethano 242

Prepared according to Example 23 from 1-(pyrimidin-5-yl)-1-(5- (4- (trifluoromethoxy)phenyl)pyridin- 2-yl)but-2-yn-1-ol (199) and iodoethane 243

Prepared according to Example 23 from 1-(pyrimidin-5-yl)-1-(5- (4- (trifluoromethoxy)phenyl)pyridin- 2-yl)ethanol and propargyl bromide 244

Prepared according to Example 23 from 1-(pyrimidin-5-yl)-1-(5- (4- (trifluoromethoxy)phenyl)pyridin- 2-yl)propan-1-ol (191) and iodoethane 246

Prepared according to Example 28 using 1-bromo-4-(1,1- difluoroethyl)benzene in step 28E 247

Prepared according to Example 28 using (4- chlorophenyl)boronic acid in step 28F (skip steps 28D-E) 248

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)but-2- yn-1-ol (118) and propargyl bromide 249

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-2-methyl-1-(pyrimidin-5- yl)propan-1-ol (163) and iodomethane 250

Prepared according to Example 23 from cyclopropyl(5-(2-fluoro- 4- (trifluoromethoxy)phenyl)pyridin- 2-yl)(pyrimidin-5-yl)methanol (117) and propargyl bromide 251

Prepared according to Example 24 using 1-(4-bromo-3- fluorophenyl)cyclobutane- carbonitrile in 24C 252

Prepared according to Example 24 using 2-(4-bromo-3,5- dimethylphenyl)-2- methylpropanenitrile in 24C. 2- (4-bromo-3,5-dimethylphenyl)- 2-methylpropanenitrile was prepared from 4-bromo-3,5- dimethylbenzaldehyde according to conditions described for 25A-25D using methanesulfonyl chloride, triethylamine, and DCM in 25B and potassium cyanide and DMF in 25C 253

Prepared according to Example 23 from 2,2-dimethyl-1- (pyrimidin-5-yl)-1-(6′-(2,2,2- trifluoroethoxy)-[3,3′-bipyridin]- 6-yl)propan-1-ol 254

Prepared according to Example 28 using 1-(4-bromo-3- methylphenyl)cyclopropane- carbonitrile in 28E 255

Prepared according to Example 23 from cyclopropyl(pyrimidin- 5-yl)(5-(4- (trifluoromethoxy)phenyl)pyridin- 2-yl)methanol and propargyl bromide 256

Prepared according to Example 28 using 2-(4-bromo-3- fluorophenyl)-2- methylpropanenitrile in 28E 257

Prepared according to Example 23 from 2,2-dimethyl-1- (pyrimidin-5-yl)-1-(5-(4-(2,2,2- trifluoroethoxy)phenyl)pyridin- 2-yl)propan-1-ol 258

Prepared according to Example 27 using ethyl magnesium bromide in 27D 259

Prepared according to Example 23 from 2-(4-(6-(1-hydroxy-2,2- dimethyl-1-(pyrimidin-5- yl)propyl)pyridin-3-yl)pheny1)-2- methylpropanenitrile using LHMDS and trimethylsilyl chloride 260

Prepared according to Example 23 from 1-(pyrimidin-5-yl)-1-(5- (4- (trifluoromethoxy)phenyl)pyridin- 2-yl)propan-l-ol (191) and propargyl bromide 261

Prepared according to Example 23 from 2,2-dimethyl-1-(5-(2- methyl-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)propan- 1-ol 262

Prepared according to Example 16 from 1-(5-bromopyridin-2- yl)-1-(5-fluoropyridin-3-yl)-2,2- dimethylpropan-1-ol (178) and (4-(2-cyanopropan-2- yl)phenyl)boronic acid in 16C. 263

Prepared according to Example 29 using 2-(4-bromo-3- methoxyphenyl)-2- methylpropanenitrile in 29F. 2- (4-bromo-3-methoxyphenyl)-2- methylpropanenitrile was prepared from 4-bromo-3- methoxybenzaldehyde according to conditions described for 29B-29E using para-toluenesulfonyl chloride in 29C and sodium hydride in 29E 264

Prepared according to Example 24 using 2-(4-bromo-3- ethylbutanenitrile in 24C. 2-(4- bromo-3-methylphenyl)-2- ethylbutanenitrile was prepared from 2-(4-bromo- 3methylphenypacetonitrile and iodoethane according to conditions described in 24A 265

Prepared according to Example 25 using 2-(4-bromo-3- chlorophenyl)-2- methylpropanenitrile in 25E. 2- (4-bromo-3-chlorophenyl)-2- methylpropanenitrile was prepared from 2-(4-bromo-3- chlorophenyl)acetonitrile according to conditions described for 25D 266

Example 27 267

Prepared according to Example 23 from 2-(4-(6-(1-hydroxy-2,2- dimethyl-1-(pyrimidin-5- yl)propyl)pyridin-3-yl)-3- methylphenyl)-2- methylpropanenitrile (156) 268

Prepared according to Example 24 using 2-(4-bromo-3- fluorophenyl)-2- ethylbutanenitrile in 24C. 2-(4- bromo-3-fluorophenyl)-2- ethylbutanenitrile was prepared from 2-(4-bromo-3- fluorophenyl)acetonitrile and iodoethane according to conditions described in 24A 269

Prepared according to Example 23 from 1-(5-(2-fluoro-4- (trifluoromethoxy)phenyl)pyridin- 2-yl)-1-(pyrimidin-5-yl)propan- 1-ol (138) and iodomethane 270

Prepared according to Example 23 from 1-(pyrimidin-5-yl)-1-(5- (trifluoromethoxy)phenyl)pyridin- 2-yl)but-2-yn-1-ol (199) and propargyl bromide 271

Prepared according to Example 16 using N-methoxy-N- methylpyrazine-2-carboxamide in 16A, tert-butylmagnesium chloride in 1613, and 2-(2-fluoro- 4-(trifluoromethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (prepared as described in 17A) in 16C 272

Prepared according to Example 23 from 2-methyl-1-(pyrimidin- 5-yl)-1-(5-(4- (trifluoromethoxy)phenyl)pyridin- 2-yl)propan-1-ol and iodoethane 273

Prepared according to Example 28 using 2-(4- (difluoromethoxy)phenyl)- 4,4,5,5-tetramethy1-1,3,2- dioxaborolane in step 28F (skip steps 28D-E) 274

Prepared according to Example 29 using 2-(4-bromo-3-fluoro-5- methylphenyl)-2- methylpropanenitrile in 29F. 2- (4-bromo-3-fluoro-5- methylphenyl)-2- methylpropanenitrile was prepared from 2-bromo-1- fluoro-5-iodo-3-methylbenzene according to conditions described for 29A-29E 275

Prepared according to Example 25 using 2-(4-bromophenoxy)- N,N,2-trimethylpropan-1-amine in 25E. 277

Example 23 278

Prepared according to Example 25 using 5-bromo-2-(2- cyanopropan-2-yl)benzonitrile in 25E. 5-bromo-2-(2- cyanopropan-2-yl)benzonitrile was prepared from 5-bromo-2- (cyanomethyl)benzonitrile according to conditions described for 25D 279

Prepared according to Example 25 using 1-(4- bromophenyl)cyclobutane- carbonitrile in 25E.

TABLE 2 Analytical Data. Compound Mass NMR (¹H, ¹³C, ¹⁹F) Number Spec IR (Thin Film; cm⁻¹) 1 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 8.57 (s, 1H), 8.43 (s, m/z 471 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.57-7.52 (m, 1H), 7.41 [M + H]⁺ (d, J = 8.7 Hz, 1H), 7.32 (dd, J = 8.7, 2.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.94-6.86 (m, 2H), 5.77 (d, J = 14.7 Hz, 1H), 5.07 (d, J = 14.7 Hz, 1H) 2 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.32-8.30 m/z 475 (m, 1H), 8.12-8.09 (m, 1H), 7.72 (dd, J = 8.7, 2.7 Hz, [M + H]⁺ 1H), 7.61 (dd, J = 8.6, 2.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.05-6.94 (m, 2H), 6.77-6.69 (m, 2H), 5.62 (s, 1H), 4.81 (d, J = 14.0 Hz, 1H), 4.73 (d, J = 14.0 Hz, 1H), 2.74-2.65 (m, 1H), 2.38-2.24 (m, 2H), 2.09 (ddd, J = 13.7, 11.8, 5.0 Hz, 1H) ¹⁹F NMR (376 MHz, CDCl₃) δ −113.02 (d, J = 6.6 Hz), −114.47 (d, J = 6.8 Hz) 3 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 1H), 9.00 (s, 2H), (m/z) 8.31 (dd, J = 2.7, 0.8 Hz, 1H), 7.68-7.58 (m, 2H), 7.46 [M + H]⁺ (dd, J = 8.7, 0.8 Hz, 1H), 7.40 (dd, J = 8.7, 2.7 Hz, 1H), calcd for 7.10-7.04 (m, 2H), 5.56 (s, 1H), 2.79 (hept, J = 6.7 Hz, C₂₀H₁₉F₃N₃O₂, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H) 390.1424; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.00 found, IR 3353, 1323, 1241 390.1402 4 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.72 (d, J = 1.1 Hz, 1H), m/z 459 8.31 (d, J = 2.6 Hz, 1H), 8.11 (t, J = 2.2 Hz, 1H), 7.74- [M + H]⁺ 7.69 (m, 1H), 7.61 (dt, J = 8.6, 2.5 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.02-6.95 (m, 4H), 5.62 (s, 1H), 4.81 (d, J = 14.0 Hz, 1H), 4.73 (dd, J = 14.0, 1.2 Hz, 1H), 2.74-2.64 (m, 1H), 2.37-2.23 (m, 2H), 2.09 (dt, J = 11.0, 6.9 Hz, 1H) ¹⁹F NMR (376 MHz, CDCl₃) δ −115.94 (d, J = 4.9 Hz) 5 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.43 (dd, J = m/z 493 1.6, 0.8 Hz, 1H), 8.34 (dd, J = 2.6, 0.6 Hz, 1H), 8.00- [M + H]⁺ 7.95 (m, 1H), 7.64 (dd, J = 8.6, 2.6 Hz, 1H), 7.53 (dd, J = 8.6, 0.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.02 (td, J = 8.7, 6.5 Hz, 1H), 6.77-6.69 (m, 2H), 5.60 (s, 1H), 4.84 (d, J = 14.0 Hz, 1H), 4.75 (d, J = 14.0 Hz, 1H), 2.76- 2.66 (m, 1H), 2.40-2.26 (m, 2H), 2.12 (ddd, J = 13.7, 11.7, 5.0 Hz, 1H) ¹⁹F NMR (376 MHz, CDCl₃) δ −61.77, −112.99 (d, J = 6.8 Hz), −114.48 (d, J = 6.8 Hz) 6 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 1H), 8.99 (s, 2H), (m/z) 8.25 (dd, J = 2.7, 0.8 Hz, 1H), 7.40 (dd, J = 8.7, 0.8 Hz, [M + H]⁺ 1H), 7.36-7.28 (m, 3H), 6.98-6.92 (m, 2H), 5.63 (s, calcd for 1H), 2.77 (p, J = 6.7 Hz, 1H), 0.95 (d, J = 6.7 Hz, 3H), C₁₉H₁₉ClN₃O₂, 0.78 (d, J = 6.6 Hz, 3H) 356.1160; IR 3342, 1486, 1473, 1240 found, 356.1156 7 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.89 (s, 2H), (m/z) 8.28 (dd, J = 2.6, 0.9 Hz, 1H), 7.38-7.33 (m, 2H), 7.32 [M + H]⁺ (d, J = 2.6 Hz, 1H), 7.29 (dd, J = 8.7, 0.9 Hz, 1H), 7.03- calcd for 6.96 (m, 2H), 5.49 (s, 1H), 1.69-1.57 (m, 1H), 0.75- C₁₉H₁₇ClN₃O₂, 0.61 (m, 2H), 0.62-0.52 (m, 1H), 0.52-0.43 (m, 1H) 354.1004; IR 3336, 1486, 1242 found, 354.1003 8 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.90 (s, 2H), (m/z) 8.30 (dd, J = 2.6, 0.8 Hz, 1H), 7.35 (dd, J = 8.7, 2.6 Hz, [M + H]⁺ 1H), 7.31 (dd, J = 8.7, 0.9 Hz, 1H), 7.29-7.21 (m, 2H), calcd for 7.10-7.03 (m, 2H), 5.48 (s, 1H), 1.67-1.60 (m, 1H), C₂₀H₁₇F₃N₃O₃, 0.74-0.61 (m, 2H), 0.61-0.53 (m, 1H), 0.53-0.45 (m, 404.1217; 1H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −58.25 404.1215 IR 3324, 1501, 1474, 1242 9 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 1H), 8.99 (s, 2H), (m/z) 8.27 (dd, J = 2.8, 0.8 Hz, 1H), 7.42 (dd, J = 8.7, 0.8 Hz, [M + H]⁺ 1H), 7.34 (dd, J = 8.7, 2.7 Hz, 1H), 7.25-7.19 (m, 2H), calcd for 7.07-6.97 (m, 2H), 5.61 (s, 1H), 2.78 (p, J = 6.7 Hz, 1H), C₂₀H₁₉F₃N₃O₃, 0.96 (d, J = 6.7 Hz, 3H), 0.78 (d, J = 6.6 Hz, 3H) 406.1373; ¹⁹F NMR (376 MHz, CDCl₃) δ −58.26 found, IR 3346, 1501, 1241 406.1374 10 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 1H), 8.99 (s, 2H), (m/z) 8.30 (dd, J = 2.8, 0.7 Hz, 1H), 8.19 (dd, J = 2.8, 0.8 Hz, [M + H]⁺ 1H), 7.46 (dd, J = 8.8, 0.8 Hz, 1H), 7.39-7.27 (m, 3H), calcd for 5.45 (s, 1H), 2.80 (p, J = 6.7 Hz, 1H), 0.96 (d, J = 6.7 Hz, C₁₈H₁₈ClN₄O₂, 3H), 0.78 (d, J = 6.6 Hz, 3H) 357.1113; IR 3358, 1567, 1454, 1261 found, 357.1114 11 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.90 (s, 2H), (m/z) 8.33 (dd, J = 2.5, 1.0 Hz, 1H), 8.23 (dd, J = 2.3, 1.3 Hz, [M + H]⁺ 1H), 7.40-7.31 (m, 4H), 5.38 (s, 1H), 1.70-1.55 (m, calcd for 1H), 0.73-0.63 (m, 2H), 0.61-0.53 (m, 1H), 0.53-0.45 C₁₈H₁₆ClN₄O₂, (m, 1H) 355.0956; IR 3330, 1567, 1454, 1261 found, 355.0952 12 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.43 (d, J = m/z 509 0.9 Hz, 1H), 8.34 (dd, J = 2.6, 0.6 Hz, 1H), 7.98 (dd, J = [M + H]⁺ 8.6, 2.5 Hz, 1H), 7.65 (dd, J = 8.6, 2.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.04-6.97 (m, 3H), 5.59 (s, 1H), 4.84 (d, J = 14.0 Hz, 1H), 4.74 (d, J = 14.0 Hz, 1H), 2.76-2.66 (m, 1H), 2.32 (tdd, J = 16.3, 11.5, 5.1 Hz, 2H), 2.11 (ddd, J = 14.1, 12.0, 5.3 Hz, 1H) ¹⁹F NMR (376 MHz, CDCl₃) δ −61.77, −115.96 13 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 1H), 9.01 (s, 2H), (m/z) 8.39 (dd, J = 2.6, 0.8 Hz, 1H), 8.06 (dd, J = 2.6, 0.7 Hz, [M + H]⁺ 1H), 7.70 (dd, J = 8.7, 2.6 Hz, 1H), 7.56 (dd, J = 8.7, 2.6 calcd for Hz, 1H), 7.46 (dd, J = 8.7, 0.8 Hz, 1H), 6.96 (dd, J = 8.7, C₁₈H₁₈ClN₄O₂, 0.7 Hz, 1H), 5.72 (s, 1H), 2.79 (hept, J = 6.7 Hz, 1H), 357.1113; 0.97 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H) found, IR 3349, 1457, 1370, 1269 357.1102 14 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.92 (s, 2H), (m/z) 8.42 (dd, J = 2.6, 0.7 Hz, 1H), 8.09 (dd, J = 2.7, 0.7 Hz, [M + H]⁺ 1H), 7.71 (dd, J = 8.7, 2.6 Hz, 1H), 7.57 (dd, J = 8.6, 2.6 calcd for Hz, 1H), 7.36 (dd, J = 8.6, 0.7 Hz, 1H), 6.99 (dd, J = 8.7, C₁₈H₁₆ClN₄O₂, 0.7 Hz, 1H), 5.56 (s, 1H), 1.66 (tt, J = 8.1, 5.3 Hz, 1H), 355.0956; 0.72-0.63 (m, 2H), 0.63-0.54 (m, 1H), 0.54-0.44 (m, found, 1H) 355.0946 IR 3342, 1457, 1370, 1269 15 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J = 1.1 Hz, 1H), m/z 491 8.42 (s, 1H), 8.35 (dd, J = 2.6, 0.5 Hz, 1H), 7.97 (dd, J = [M + H]⁺ 8.6, 2.0 Hz, 1H), 7.64 (dt, J = 8.6, 2.4 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.23-7.17 (m, 2H), 7.11 (d, J = 8.7 Hz, 1H), 7.03-6.98 (m, 2H), 5.54 (s, 1H), 4.86 (d, J = 14.0 Hz, 1H), 4.75 (d, J = 14.0 Hz, 1H), 2.77-2.67 (m, 1H), 2.33-2.23 (m, 2H), 2.15 (dt, J = 13.8, 9.3 Hz, 1H) ¹⁹F NMR (376 MHz, CDCl₃) δ −61.76 16 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 9.01 (s, 2H), (m/z) 8.33 (dd, J = 2.7, 0.8 Hz, 1H), 7.70-7.61 (m, 2H), 7.50 [M + H]⁺ (dd, J = 8.7, 0.8 Hz, 1H), 7.43 (dd, J = 8.7, 2.7 Hz, 1H), calcd for 7.08-6.98 (m, 2H), 5.46 (s, 1H), 2.81 (p, J = 6.6 Hz, 1H), C₂₀H₁₉N₄O₂, 0.97 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H) 347.1503; IR 3356, 2228, 1502, 1472, 1242 found, 347.1506 17 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.91 (s, 2H), (m/z) 8.34 (dd, J = 2.7, 0.8 Hz, 1H), 7.68-7.59 (m, 2H), 7.41 [M + H]⁺ (dd, J = 8.6, 2.7 Hz, 1H), 7.35 (dd, J = 8.6, 0.8 Hz, 1H), calcd for 7.14-7.05 (m, 2H), 5.46 (s, 1H), 1.70-1.60 (m, 1H), C₂₀H₁₇F₃N₃O₂, 0.76-0.62 (m, 2H), 0.62-0.53 (m, 1H), 0.54-0.41 (m, 388.1267; 1H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −61.99 388.1252 IR 3333, 1323, 1241 18 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.91 (s, 2H), (m/z) 8.36 (dd, J = 2.6, 0.8 Hz, 1H), 7.72-7.64 (m, 2H), 7.44 [M + H]⁺ (dd, J = 8.6, 2.6 Hz, 1H), 7.39 (dd, J = 8.6, 0.9 Hz, 1H), calcd for 7.13-7.03 (m, 2H), 5.39 (s, 1H), 1.72-1.61 (m, 1H), C₂₀H₁₇N₄O₂, 0.76-0.63 (m, 2H), 0.65-0.55 (m, 1H), 0.55-0.46 (m, 345.1346; 1H) found, IR 3350, 2228, 1502, 1473, 1243 345.1334 19 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.16 (dd, J = (m/z) 2.7, 0.7 Hz, 1H), 7.72-7.65 (m, 2H), 7.62 (dd, J = 8.6, [M + H]⁺ 0.8 Hz, 1H), 7.47 (dd, J = 8.6, 2.7 Hz, 1H), 7.08-7.00 calcd for (m, 2H), 5.08 (s, 1H), 5.01 (d, J = 14.1 Hz, 1H), 4.75 (d, C₁₈H₁₇N₆O₂, J = 14.1 Hz, 1H), 1.36-1.24 (m, 1H), 0.67-0.56 (m, 1H), 349.1408; 0.52 (dddd, J = 9.3, 8.1, 6.0, 4.3 Hz, 1H), 0.45-0.24 (m, found, 2H) 349.1413 IR 3362, 2228, 1502, 1477, 1242 20 HRMS-ESI (m/z) ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.93 (s, 2H), [M + H]⁺ 8.31 (dd, J = 2.8, 0.7 Hz, 1H), 7.41 (dd, J = 8.7, 0.8 Hz, calcd for 1H), 7.37-7.28 (m, 3H), 6.99-6.93 (m, 2H), 5.68 (ddt, C₁₉H₁₇ClN₃O₂, J = 17.2, 10.2, 7.0 Hz, 1H), 5.24-5.09 (m, 2H), 4.90 (s, 354.1004; 1H), 3.20-2.97 (m, 2H) found, IR 3280, 1486, 1473, 1236 354.1006 21 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.91 (s, 2H), (m/z) 8.29 (dd, J = 2.3, 1.2 Hz, 1H), 7.40-7.30 (m, 4H), 7.06- [M + H]⁺ 6.90 (m, 2H), 5.81 (ddt, J = 16.9, 10.2, 6.5 Hz, 1H), 5.61 calcd for (s, 1H), 5.07-4.91 (m, 2H), 2.47-2.29 (m, 2H), 2.25- C₂₀H₁₉ClN₃O₂, 2.08 (m, 1H), 2.05-1.91 (m, 1H) 368.1160; IR 3262, 1486, 1474, 1237 found, 368.1141 22 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.91 (s, 2H), (m/z) 8.30 (dd, J = 2.2, 1.3 Hz, 1H), 7.37-7.33 (m, 2H), 7.28- [M + H]⁺ 7.19 (m, 2H), 7.09-7.01 (m, 2H), 5.81 (ddt, J = 16.8, calcd for 10.2, 6.5 Hz, 1H), 5.59 (s, 1H), 5.04-4.91 (m, 2H), 2.47- C₂₁H₁₉F₃N₃O₃, 2.29 (m, 2H), 2.24-2.10 (m, 1H), 2.06-1.89 (m, 1H) 418.1373; ¹⁹F NMR (376 MHz, CDCl₃) δ −58.26 found, IR 3274, 1502, 1249, 1187 418.1382 23 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.22 (dd, J = (m/z) 2.7, 0.7 Hz, 1H), 7.74-7.61 (m, 2H), 7.52 (dd, J = 8.7, [M + H]⁺ 0.8 Hz, 1H), 7.40 (dd, J = 8.6, 2.7 Hz, 1H), 7.04-6.97 calcd for (m, 2H), 5.10 (d, J = 0.7 Hz, 1H), 5.01 (dd, J = 14.1, 0.8 C₁₉H₁₉N₆O₂, Hz, 1H), 4.81 (d, J = 14.0 Hz, 1H), 1.98 (dd, J = 14.2, 6.4 363.1564; Hz, 1H), 1.77 (dd, J = 14.2, 7.1 Hz, 1H), 0.83-0.63 (m, found, 1H), 0.52 (ddd, J = 13.5, 9.1, 5.0 Hz, 1H), 0.37 (dddd, J = 363.1568 9.3, 8.0, 5.6, 4.4 Hz, 1H), 0.28-0.07 (m, 1H), −0.04-−0.22 (m, 1H) IR 3377, 2228, 1502, 1479, 1242 24 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 8.12 (dd, J = (m/z) 2.7, 0.8 Hz, 1H), 7.71-7.64 (m, 2H), 7.48 (dd, J = 8.7, [M + H]⁺ 0.8 Hz, 1H), 7.41 (dd, J = 8.6, 2.7 Hz, 1H), 7.05-6.93 calcd for (m, 2H), 5.30 (t, J = 1.0 Hz, 1H), 5.00 (d, J = 14.0 Hz, C₁₈H₁₉N₆O₂, 1H), 4.78 (d, J = 14.0 Hz, 1H), 2.27 (hept, J = 6.8 Hz, 351.1564; 1H), 1.17 (d, J = 6.7 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H) found, IR 3363, 2228, 1478, 1242 351.1569 25 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.99 (s, 1H), 8.61 (dd, J = m/z 326 2.2, 0.7 Hz, 1H), 8.39 (s, 2H), 7.90 (dd, J = 8.2, 2.2 Hz, [M + H]⁺ 1H), 7.50-7.44 (m, 5H), 5.10 (s, 1H), 3.13 (d, J = 13.7 Hz, 1H), 3.07 (d, J = 13.7 Hz, 1H), 1.67 (s, 3H) ¹³C NMR (101 MHz, CDCl₃) δ 161.91, 158.03, 156.91, 145.77, 135.53, 135.44, 134.62, 134.38, 130.46, 129.37, 128.35, 119.25, 73.62, 44.28, 28.79 26 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H), 8.57 (d, J = m/z 408 1.6 Hz, 1H), 7.82 (dd, J = 8.2, 2.3 Hz, 1H), 7.57 (d, J = [M + H]⁺ 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 5.82 (brs, 1H), 5.42 (d, J = 14.1 Hz, 1H), 4.77 (d, J = 14.1 Hz, 1H), 1.06 (s, 9H) 27 HRMS-ESI ¹H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 2H), 9.09 (m/z) (s, 1H), 8.76 (dd, J = 2.4, 0.9 Hz, 1H), 7.94 (dd, J = 8.4, [M + H]⁺ 2.4 Hz, 1H), 7.86 (dd, J = 8.4, 0.9 Hz, 1H), 7.66-7.57 (m, calcd for 2H), 7.39-7.32 (m, 2H), 6.16 (s, 1H), 1.09 (s, 9H) C₂₁H₂₁F₃N₃O₂, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.80 404.1580; IR 3263, 1256, 1210, 1166 found, 404.1582 28 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 8.71 (s, 1H), 8.52 (d, J = m/z 494 2.1 Hz, 1H), 7.90 (dd, J = 8.2, 2.3 Hz, 1H), 7.60-7.50 [M + H]⁺ (m, 3H), 7.32 (d, J = 8.3 Hz, 2H), 7.14 (t, J = 8.1 Hz, 1H), 7.06-6.87 (m, 2H), 5.54 (s, 1H), 5.13 (d, J = 14.1 Hz, 1H), 4.72 (d, J = 14.1 Hz, 1H), 3.23 (s, 2H) 29 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.96 (s, 2H), (m/z) 8.27 (dd, J = 2.7, 0.7 Hz, 1H), 7.46 (dd, J = 8.7, 0.7 Hz, [M + H]⁺ 1H), 7.38-7.33 (m, 2H), 7.32 (dd, J = 8.7, 2.7 Hz, 1H), calcd for 7.06-6.92 (m, 2H), 6.07 (s, 1H), 1.30 (s, 9H) C₂₂H₂₁ClN₃O₂, IR 3246, 1486, 1472, 1237 394.1317; found, 394.1321 30 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.90 (s, 2H), (m/z) 8.29 (dd, J = 2.0, 1.5 Hz, 1H), 7.37-7.31 (m, 4H), 6.99- [M + H]⁺ 6.94 (m, 2H), 5.55 (s, 1H), 2.31 (hept, J = 7.0 Hz, 2H), calcd for 0.90 (t, J = 7.3 Hz, 3H) C₂₂H₂₀ClN₃O₂, IR 3308, 1486, 1474, 1238 342.1004; found, 342.1010 31 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.96 (s, 2H), (m/z) 8.29 (dd, J = 2.7, 0.7 Hz, 1H), 7.48 (dd, J = 8.7, 0.7 Hz, [M + H]⁺ 1H), 7.34 (dd, J = 8.7, 2.7 Hz, 1H), 7.28-7.20 (m, 2H), calcd for 7.10-7.03 (m, 2H), 6.06 (s, 1H), 1.31 (s, 9H) C₂₃H₂₁F₃N₃O₃, ¹⁹F NMR (376 MHz, CDCl₃) δ −58.25 444.1530; IR 3181, 1501, 1471, 1238, 1185 found, 444.1523 32 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.90 (s, 2H), (m/z) 8.31 (dd, J = 2.2, 1.3 Hz, 1H), 7.38-7.32 (m, 2H), 7.26- [M + H]⁺ 7.20 (m, 2H), 7.09-7.01 (m, 2H), 5.53 (s, 1H), 2.31 calcd for (hept, J = 7.0 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H) C₁₉H₁₇F₃N₃O₃, ¹⁹F NMR (376 MHz, CDCl₃) δ −58.26 392.1217; IR 3278, 1501, 1473, 1239, 1185 found, 392.1213 33 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.97 (s, 2H), (m/z) 8.33 (dd, J = 2.8, 0.7 Hz, 1H), 7.69-7.61 (m, 2H), 7.52 [M + H]⁺ (dd, J = 8.7, 0.8 Hz, 1H), 7.39 (dd, J = 8.6, 2.7 Hz, 1H), calcd for 7.18-7.06 (m, 2H), 6.02 (s, 1H), 1.31 (s, 9H) C₂₃H₂₁F₃N₃O₂, ¹⁹F NMR (376 MHz, CDCl₃) δ −62.02 428.1580; IR 3191, 1471, 1325, 1240 found, 428.1582 34 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.91 (s, 2H), (m/z) 8.35 (dd, J = 2.5, 1.0 Hz, 1H), 7.70-7.58 (m, 2H), 7.45- [M + H]⁺ 7.34 (m, 2H), 7.12-7.03 (m, 2H), 5.48 (s, 1H), 2.33 calcd for (hept, J = 7.0 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H) C₁₉H₁₇F₃N₃O₂, ¹⁹F NMR (376 MHz, CDCl₃) δ −62.00 376.1267; IR 3289, 1474, 1325, 1241 found, 376.1268 35 HRMS-ESI (m/z) ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.96 (s, 2H), [M + H]⁺ 8.32 (dd, J = 2.8, 0.7 Hz, 1H), 8.22 (dd, J = 2.5, 1.2 Hz, calcd for 1H), 7.52 (dd, J = 8.7, 0.7 Hz, 1H), 7.40-7.32 (m, 3H), C₂₁H₂₀ClN₄O₂, 5.94 (s, 1H), 1.31 (s, 9H) 395.1269; IR 3191, 1568, 1454, 1262 found, 395.1260 36 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.90 (s, 2H), (m/z) 8.33 (dd, J = 2.4, 1.1 Hz, 1H), 8.20 (dd, J = 2.8, 0.9 Hz, [M + H]⁺ 1H), 7.44-7.29 (m, 4H), 5.38 (s, 1H), 2.42-2.22 (m, calcd for 2H), 0.90 (t, J = 7.3 Hz, 3H) C₁₇H₁₆ClN₄O₂, IR 3325, 1567, 1454, 1261 343.0956; found, 343.0952 37 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.96 (s, 2H), (m/z) 8.38 (dd, J = 2.8, 0.7 Hz, 1H), 7.72-7.61 (m, 2H), 7.53 [M + H]⁺ (dd, J = 8.7, 0.7 Hz, 1H), 7.41 (dd, J = 8.6, 2.7 Hz, 1H), calcd for 7.10-6.99 (m, 2H), 5.68 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), C₂₀H₁₇N₄O₂, 5.30-5.13 (m, 2H), 4.68 (s, 1H), 3.27-2.97 (m, 2H) 345.1346; IR 3261, 2228, 1502, 1472, 1238 found, 345.1351 38 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 8.51 (dd, J = m/z 354 2.2, 0.7 Hz, 1H), 8.32 (s, 2H), 7.87 (dd, J = 8.2, 2.2 Hz, [M + H]⁺ 1H), 7.48-7.41 (m, 5H), 5.21 (s, 1H), 3.37 (d, J = 13.8 Hz, 1H), 2.98 (d, J = 13.8 Hz, 1H), 2.25 (hept, J = 6.6 Hz, 1H), 1.19 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H) ¹³C NMR (101 MHz, CDCl₃) δ 160.28, 157.95, 156.57, 145.34, 135.33, 135.19, 134.57, 134.03, 130.85, 129.33, 128.30, 119.85, 78.08, 40.21, 38.01, 17.47, 16.89 39 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.97 (s, 1H), 8.56 (d, J = m/z 352 2.2 Hz, 1H), 8.43 (s, 2H), 7.92 (dd, J = 8.2, 2.2 Hz, 1H), [M + H]⁺ 7.57 (d, J = 8.2 Hz, 1H), 7.47 (q, J = 8.5 Hz, 4H), 5.04 (s, 1H), 3.24 (d, J = 13.8 Hz, 1H), 3.14 (d, J = 13.8 Hz, 1H), 1.34 (tt, J = 8.2, 5.2 Hz, 1H), 0.61 (td, J = 9.9, 5.1 Hz, 1H), 0.53-0.44 (m, 1H), 0.34 (td, J = 9.8, 5.4 Hz, 1H), 0.29-0.21 (m, 1H) ¹³C NMR (101 MHz, CDCl₃) δ 161.63, 158.18, 156.83, 145.49, 135.62, 135.56, 134.67, 134.47, 130.59, 129.45, 128.43, 119.70, 73.49, 43.33, 20.97, 1.62, 0.00 40 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.94 (s, 2H), (m/z) 8.27 (dd, J = 2.8, 0.8 Hz, 1H), 7.44 (dd, J = 8.6, 0.7 Hz, [M + H]⁺ 1H), 7.38-7.33 (m, 2H), 7.31 (dd, J = 8.7, 2.7 Hz, 1H), calcd for 7.02-6.93 (m, 2H), 6.02 (s, 1H), 1.42-1.32 (m, 1H), C₂₁H₁₇ClN₃O₂, 0.90-0.81 (m, 2H), 0.82-0.74 (m, 2H) 378.1004; IR 3157, 2239, 1485, 1471, 1238 found, 378.1004 41 HRMS-ESI ¹H NMR (400 MHz, Chloroform-d) δ 9.12 (s, 1H), 8.93 (m/z) (s, 2H), 8.21 (dd, J = 2.7, 0.7 Hz, 1H), 7.49-7.41 (m, [M + H]⁺ 1H), 7.39-7.29 (m, 3H), 7.19 (t, J = 8.1 Hz, 1H), 7.03- calcd for 6.97 (m, 1H), 6.97-6.89 (m, 3H), 5.40 (d, J = 0.7 Hz, C₂₃H₁₇C₁₂FN₃O₂, 1H), 3.71-3.52 (m, 2H) 456.0676; ¹⁹F NMR (376 MHz, CDCl₃) δ −114.17 found, IR 3220, 1486, 1410, 1239 456.0678 42 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 8.68 (s, 1H), 8.05 (d, J = m/z 460 2.7 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, [M + H]⁺ 2H), 7.29 (dd, J = 9.0, 3.0 Hz, 1H), 7.13 (t, J = 8.1 Hz, 1H), 7.06-6.96 (m, 2H), 6.92 (d, J = 8.4 Hz, 2H), 5.34 (s, 1H), 5.08 (d, J = 14.4 Hz, 1H), 4.68 (d, J = 14.4 Hz, 1H), 3.19 (s, 2H) 43 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 1H), 8.10 (d, J = m/z 374 3.2 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 8.8 Hz, [M + H]⁺ 2H), 7.22 (dd, J = 8.8, 3.2 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 5.61 (brs, 1H), 5.35 (d, J = 14.0 Hz, 1H), 4.73 (d, J = 14.0 Hz, 1H), 1.03 (s, 9H) 44 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.66-8.60 (m, 3H), 8.30 m/z 370 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.40-7.30 [M + H]⁺ (m, 3H), 7.01 (d, J = 8.8 Hz, 2H), 4.73 (s, 1H), 1.07 (s, 9H) 45 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.94 (s, 2H), (m/z) 8.32 (dd, J = 2.7, 0.8 Hz, 1H), 7.43 (dd, J = 8.7, 0.8 Hz, [M + H]⁺ 1H), 7.33 (dd, J = 8.7, 2.8 Hz, 1H), 7.22 (s, 2H), 7.08- calcd for 7.00 (m, 2H), 5.09 (s, 1H), 2.36-2.17 (m, 2H), 0.77- C₂₁H₁₉F₃N₃O₃, 0.62 (m, 1H), 0.52-0.28 (m, 2H), 0.14-0.02 (m, 1H), 418.1373; 0.00-−0.02 (m, 1H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −58.26 418.1367 IR 3353, 2253, 1502, 1475, 1250 46 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.97 (s, 1H), 8.62 (dd, J = m/z 380 2.2, 0.9 Hz, 1H), 8.46 (s, 2H), 8.00 (dd, J = 8.3, 2.3 Hz, [M + H]⁺; 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.47 (s, 4H), 6.36 (s, 1H), m/z 378 3.54 (d, J = 14.2 Hz, 1H), 3.33 (d, J = 14.2 Hz, 1H) ([M − H]⁻) ¹⁹F NMR (376 MHz, CDCl₃) δ −79.12 47 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.96 (s, 2H), (m/z) 8.33 (dd, J = 2.7, 0.7 Hz, 1H), 7.69-7.59 (m, 2H), 7.50 [M + H]⁺ (dd, J = 8.7, 0.8 Hz, 1H), 7.39 (dd, J = 8.6, 2.7 Hz, 1H), calcd for 7.16-7.06 (m, 2H), 5.96 (s, 1H), 1.44-1.33 (m, 1H), C₂₂H₁₇F₃N₃O₂, 0.92-0.82 (m, 2H), 0.83-0.74 (m, 2H) 412.1267; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.02 found, IR 3152, 2237, 1325, 1241 412.1271 48 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.95 (s, 2H), (m/z) 8.28 (dd, J = 2.7, 0.7 Hz, 1H), 7.46 (dd, J = 8.6, 0.8 Hz, [M + H]⁺ 1H), 7.40-7.28 (m, 1H), 7.29-7.20 (m, 2H), 7.11-7.01 calcd for (m, 2H), 6.00 (s, 1H), 1.44-1.31 (m, 1H), 0.90-0.82 (m, C₂₂H₁₇F₃N₃O₃, 2H), 0.82-0.74 (m,2H) 428.1217; ¹⁹F NMR (376 MHz, CDCl₃) δ −58.25 found, IR 3167, 2238, 1501, 1471 428.1222 49 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.98 (s, 2H), (m/z) 8.41 (dd, J = 2.5, 0.9 Hz, 1H), 8.09 (dd, J = 2.7, 0.7 Hz, [M + H]⁺ 1H), 7.72 (dd, J = 8.7, 2.7 Hz, 1H), 7.57 (dd, J = 8.6, 2.5 calcd for Hz, 1H), 7.53 (dd, J = 8.6, 0.9 Hz, 1H), 6.99 (dd, J = 8.7, C₂₁H₂₀ClN₄O₂, 0.7 Hz, 1H), 6.16 (s, 1H), 1.31 (s, 9H) 395.1269; IR 3167, 2240, 1457, 1370, 1267 found, 395.1278 50 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.98 (s, 2H), (m/z) 8.39 (dd, J = 2.6, 0.8 Hz, 1H), 7.97 (dt, J = 2.5, 0.8 Hz, [M + H]⁺ 1H), 7.59-7.53 (m, 2H), 7.49 (dd, J = 8.6, 0.8 Hz, 1H), calcd for 6.92 (d, J = 8.3 Hz, 1H), 6.24 (s, 1H), 2.31 (d, J = 0.7 Hz, C₂₂H₂₃N₄O₂, 3H), 1.31 (s, 9H) 375.1816; IR 3177, 2237, 1466, 1376, 1238 found, 375.1820 51 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 8.58 (d, J = m/z 368 1.6 Hz, 1H), 8.45 (s, 2H), 7.83 (dd, J = 8.3, 2.3 Hz, 1H), [M + H]⁺ 7.50 (dd, J = 8.3, 0.8 Hz, 1H), 7.48-7.42 (m, 4H), 5.61 (s, 1H), 3.31 (q, J = 14.1 Hz, 2H), 1.05 (s, 9H) ¹³C NMR (101 MHz, CDCl₃) δ 158.40, 156.42, 145.27, 135.28, 134.58, 134.11, 133.94, 131.32, 129.33, 128.27, 121.66, 79.83, 39.56, 35.05, 25.94 52 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 8.53-8.50 m/z 394 (m, 1H), 8.32 (s, 2H), 7.87 (dd, J = 8.2, 2.3 Hz, 1H), 7.48- [M + H]⁺ 7.40 (m, 5H), 5.22 (s, 1H), 3.38 (d, J = 13.8 Hz, 1H), 2.97 (d, J = 13.7 Hz, 1H), 2.16-2.09 (m, 1H), 1.88 (s, 2H), 1.67 (s, 4H), 1.14 (s, 4H) ¹³C NMR (101 MHz, CDCl₃) δ 160.27, 157.99, 156.55, 145.33, 135.35, 135.13, 134.55, 133.97, 130.89, 129.32, 128.29, 119.97, 78.11, 48.12, 39.64, 27.33, 26.76, 26.58, 26.47, 26.26 53 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 1H), 9.00 (s, 2H), (m/z) 8.37 (dd, J = 2.6, 0.7 Hz, 1H), 7.95 (dt, J = 2.5, 0.8 Hz, [M + H]⁺ 1H), 7.54 (m, 2H), 7.43 (dd, J = 8.7, 0.8 Hz, 1H), 6.89 (d, calcd for J = 8.3 Hz, 1H), 5.81 (s, 1H), 2.85-2.69 (m, 1H), 2.29 (s, C₁₉H₂₁N₄O₂, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H) 337.1659; IR 3339, 1470, 1377, 1241 found, 337.1662 54 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.92 (s, 2H), (m/z) 8.42 (dd, J = 2.6, 0.7 Hz, 1H), 8.08 (dd, J = 2.7, 0.7 Hz, [M + H]⁺ 1H), 7.71 (dd, J = 8.7, 2.6 Hz, 1H), 7.56 (dd, J = 8.6, 2.7 calcd for Hz, 1H), 7.39 (dd, J = 8.6, 0.8 Hz, 1H), 6.98 (dd, J = 8.7, C₁₇H₁₆ClN₄O₂, 0.7 Hz, 1H), 5.63 (s, 1H), 2.47-2.22 (m, 2H), 0.92 (t, J = 343.0956; 7.3 Hz, 3H) found, IR 3219, 1463, 1373, 1276 343.0959 55 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.92 (s, 2H), (m/z) 8.41 (dd, J = 2.7, 0.7 Hz, 1H), 7.96 (dt, J = 2.5, 0.8 Hz, [M + H]⁺ 1H), 7.62-7.47 (m, 2H), 7.35 (dd, J = 8.6, 0.7 Hz, 1H), calcd for 6.90 (d, J = 8.3 Hz, 1H), 5.72 (s, 1H), 2.39-2.25 (m, 5H), C₁₈H₁₉N₄O₂, 0.92 (t, J = 7.3 Hz, 3H) 323.1503; IR 3251, 1471, 1412, 1380, 1240 found, 323.1508 56 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 8.50 (dd, J = m/z 380 2.2, 0.7 Hz, 1H), 8.29 (s, 2H), 7.88 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.49-7.42 (m, 5H), 5.25 (s, 1H), 3.30 (d, J = 13.8 Hz, 1H), 3.02 (d, J = 13.8 Hz, 1H), 2.54 (p, J = 8.7 Hz, 1H), 2.01-1.83 (m, 2H), 1.80-1.42 (m, 4H), 1.24-1.07 (m, 2H) ¹³C NMR (101 MHz, CDCl₃) δ 160.83, 157.91, 156.63, 145.24, 135.36, 135.30, 134.56, 134.02, 130.57, 129.33, 128.30, 119.79, 76.94, 50.03, 41.88, 27.04, 26.95, 26.07, 25.72 57 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.85 (s, 1H), 8.57 (d, J = m/z 382 2.0 Hz, 1H), 8.43 (s, 2H), 7.83 (dd, J = 8.3, 2.3 Hz, 1H), [M + H]⁺ 7.50 (dd, J = 8.3, 0.5 Hz, 1H), 7.48-7.41 (m, 4H), 5.64 (s, 1H), 3.35 (d, J = 13.9 Hz, 1H), 3.28 (d, J = 13.8 Hz, 1H), 1.54 (dq, J = 14.9, 7.5 Hz, 1H), 1.37-1.28 (m, 1H), 1.01 (s, 3H), 1.00 (s, 3H), 0.85 (t, J = 7.5 Hz, 3H) ¹³C NMR (101 MHz, CDCl₃) δ 158.45, 156.39, 145.21, 135.28, 134.58, 134.05, 133.90, 131.33, 129.33, 128.26, 121.92, 80.54, 42.31, 35.06, 29.14, 21.34, 8.75 58 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 9.02 (s, 2H), (m/z) 8.58 (dd, J = 2.5, 0.8 Hz, 1H), 7.86 (dd, J = 8.5, 2.5 Hz, [M + H]⁺ 1H), 7.70 (ddd, J = 2.9, 1.5, 0.8 Hz, 1H), 7.65 (dd, J = 8.5, calcd for 0.8 Hz, 1H), 7.55 (dd, J = 9.7, 2.7 Hz, 1H), 6.75 (dt, J = C₁₉H₁₈F₃N₄O₂, 9.8, 0.8 Hz, 1H), 5.27 (s, 1H), 2.89 (hept, J = 6.7 Hz, 1H), 391.1376; 0.98 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −62.80 391.1377 IR 3384, 1682, 1332 59 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.76 (dd, J = 2.4, 0.9 Hz, 1H), 7.94 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.84 (dd, J = 8.4, 0.9 Hz, 1H), 7.65-7.55 (m, 2H), calcd for 7.36-7.20 (m, 2H), 6.57 (t, J = 73.5 Hz, 1H), 6.21 (s, C₂₁H₂₂F₂N₃O₂, 1H), 1.09 (s, 9H) 386.1675; ¹⁹F NMR (376 MHz, CDCl₃) δ −81.09 found, IR 3276, 1738, 1127 386.1679 60 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.94 (s, 2H), (m/z) 8.73 (dd, J = 2.3, 0.9 Hz, 1H), 7.89 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.65-7.53 (m, 2H), 7.39 (dd, J = 8.2, 0.9 Hz, 1H), calcd for 7.27 (s, 2H), 6.58 (t, J = 73.5 Hz, 1H), 5.75 (s, 1H), 1.68 C₂₀H₁₈F₂N₃O₂, (tt, J = 8.3, 5.4 Hz, 1H), 0.78-0.64 (m, 2H), 0.64-0.55 370.1362; (m, 1H), 0.55-0.44 (m, 1H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −81.09 370.1364 IR 3326, 1563, 1410, 1124 61 ESI-APCI-MS ¹H NMR (300 MHz, CDCl₃) δ 8.71 (s, 1H), 8.53 (d, J = m/z 394 2.2 Hz, 1H), 7.88 (dd, J = 8.2, 2.3 Hz, 1H), 7.54 (d, J = [M + H]⁺ 9.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 5.56 (s, 1H), 5.06 (d, J = 14.0 Hz, 1H), 4.81 (d, J = 14.0 Hz, 1H), 2.32-2.18 (m, 1H), 1.16 (d, J = 6.7 Hz, 3H), 0.76 (d, J = 6.7 Hz, 3H) 62 ESI-APCI-MS ¹H NMR (300 MHz, DMSO-d₆) δ 8.72 (br s, 1H), 8.50 (s, m/z 409 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), [M + H]⁺ 7.78 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 5.20-4.60 (m, 5H), 2.32-2.18 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H), 0.74 (d, J = 6.5 Hz, 3H) 63 HRMS-ESI ¹H NMR (400 MHz, Chloroform-d) δ 9.09 (s, 1H), 9.03 (m/z) (s, 2H), 8.70 (dd, J = 2.3, 0.9 Hz, 1H), 7.89 (dd, J = 8.3, [M + H]⁺ 2.3 Hz, 1H), 7.60-7.54 (m, 2H), 7.52 (dd, J = 8.3, 0.9 Hz, calcd for 1H), 7.38-7.29 (m, 2H), 5.88 (s, 1H), 2.82 (hept, J = 6.7 C₂₀H₁₉F₃N₃O₂, Hz, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H) 390.1424; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 found, IR 3326, 1563, 1410, 1124 390.1427 64 ESI-APCI-MS ¹H NMR (300 MHz, DMSO-d₆) δ 9.09 (s, 1H), 9.03 (s, m/z 405 2H), 8.68 (d, J = 2.2 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), [M + H]⁺ 7.87 (dd, J = 8.4, 2.4 Hz, 1H), 7.82 (dd, J = 8.4, 2.4 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 5.81 (s, 1H), 4.81 (q, J = 8.5 Hz, 2H), 2.90-2.76 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H) 65 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.76 (dd, J = 2.4, 0.9 Hz, 1H), 7.94 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.84 (dd, J = 8.4, 0.9 Hz, 1H), 7.59-7.41 (m, 4H), calcd for 6.19 (s, 1H), 1.08 (s, 9H) C₂₀H₂₁ClN₃O, IR 3251, 1558, 1469, 1409, 1365 354.1368; found, 354.1368 66 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.93 (s, 2H), (m/z) 8.73 (dd, J = 2.3, 0.9 Hz, 1H), 7.89 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.61-7.43 (m, 4H), 7.38 (dd, J = 8.2, 0.9 Hz, 1H), calcd for 5.74 (s, 1H), 1.68 (tt, J = 8.1, 5.3 Hz, 1H), 0.78-0.64 (m, C₁₉H₁₇ClN₃O, 2H), 0.63-0.55 (m, 1H), 0.49 (tdd, J = 9.1, 6.1, 4.4 Hz, 338.1055; 1H) found, IR 3324, 1562, 1471, 1409 338.1057 67 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 8.94 (s, 2H), (m/z) 8.60 (dd, J = 2.5, 0.8 Hz, 1H), 7.87 (dd, J = 8.5, 2.5 Hz, [M + H]⁺ 1H), 7.74 (s, 1H), 7.57 (dd, J = 9.7, 2.7 Hz, 1H), 7.54- calcd for 7.47 (m, 1H), 6.77 (dt, J = 9.7, 0.8 Hz, 1H), 5.34 (s, 1H), C₁₉H₁₆F₃N₄O₂, 1.76-1.63 (m, 1H), 0.79-0.67 (m, 2H), 0.62 (dt, J = 9.5, 389.1220; 4.8 Hz, 1H), 0.57-0.46 (m, 1H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −62.79 389.1215 IR 3365, 1683, 1332 68 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 8.58 (d, J = m/z 400 1.6 Hz, 1H), 8.45 (s, 2H), 7.83 (dd, J = 8.3, 2.3 Hz, 1H), [M + H]⁺ 7.55-7.48 (m, 3H), 7.22 (t, J = 5.8 Hz, 2H), 6.56 (t, J = 73.6 Hz, 1H), 5.61 (s, 1H), 3.31 (q, J = 14.0 Hz, 2H), 1.05 (s, 9H) ¹⁹F NMR (376 MHz, CDCl₃) δ −81.02 69 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 9.02 (s, 2H), (m/z) 8.41 (dd, J = 2.6, 0.7 Hz, 1H), 7.69 (dd, J = 8.1, 7.6 Hz, [M + H]⁺ 1H), 7.61 (dd, J = 8.7, 2.7 Hz, 1H), 7.47 (dd, J = 8.7, 0.8 calcd for Hz, 1H), 7.09 (dd, J = 7.6, 0.6 Hz, 1H), 6.89 (dd, J = 8.1, C₁₈H₁₈ClN₄O₂, 0.7 Hz, 1H), 5.72 (s, 1H), 2.80 (hept, J = 6.7 Hz, 1H), 357.1113; 0.97 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H) found, IR 3346, 1566, 1427, 1283 357.1114 70 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.93 (s, 2H), (m/z) 8.45 (dd, J = 2.7, 0.7 Hz, 1H), 7.70 (dd, J = 8.1, 7.6 Hz, [M + H]⁺ 1H), 7.61 (dd, J = 8.6, 2.7 Hz, 1H), 7.39 (dd, J = 8.7, 0.8 calcd for Hz, 1H), 7.10 (dd, J = 7.6, 0.7 Hz, 1H), 6.91 (dd, J = 8.1, C₁₇H₁₆ClN₄O₂, 0.7 Hz, 1H), 5.64 (s, 1H), 2.34 (hept, J = 7.0 Hz, 2H), 343.0956; 0.92 (t, J = 7.3 Hz, 3H) found, IR 3272, 1566, 1427, 1284 343.0957 71 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.99 (s, 2H), (m/z) 8.44 (dd, J = 2.6, 0.8 Hz, 1H), 7.71 (dd, J = 8.1, 7.6 Hz, [M + H]⁺ 1H), 7.61 (dd, J = 8.6, 2.6 Hz, 1H), 7.53 (dd, J = 8.6, 0.8 calcd for Hz, 1H), 7.11 (dd, J = 7.6, 0.7 Hz, 1H), 6.92 (dd, J = 8.1, C₂₁H₂₀ClN₄O₂, 0.7 Hz, 1H), 6.15 (s, 1H), 1.32 (s, 9H) 395.1269; IR 3172, 2243, 1567, 1428 found, 395.1274 72 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.93 (s, 2H), (m/z) 8.44 (dd, J = 2.6, 0.7 Hz, 1H), 7.71 (dd, J = 8.1, 7.6 Hz, [M + H]⁺ 1H), 7.61 (dd, J = 8.6, 2.6 Hz, 1H), 7.37 (dd, J = 8.6, 0.7 calcd for Hz, 1H), 7.11 (dd, J = 7.6, 0.7 Hz, 1H), 6.92 (dd, J = 8.1, C₁₈H₁₆ClN₄O₂, 0.7 Hz, 1H), 5.56 (s, 1H), 1.66 (tt, J = 8.1, 5.3 Hz, 1H), 355.0956; 0.74-0.64 (m, 2H), 0.64-0.55 (m, 1H), 0.55-0.46 (m, found, 1H) 355.0960 IR 3328, 1564, 1427, 1282, 1161 73 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.94 (s, 2H), (m/z) 8.73 (dd, J = 2.3, 0.9 Hz, 1H), 7.90 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.65-7.56 (m, 2H), 7.40 (dd, J = 8.2, 0.9 Hz, 1H), calcd for 7.38-7.32 (m, 2H), 5.72 (s, 1H), 1.68 (tt, J = 8.2, 5.3 Hz, C₂₀H₁₇F₃N₃O₂, 1H), 0.71 (dddd, J = 13.4, 12.3, 9.5, 4.2 Hz, 2H), 0.64- 388.1267; 0.55 (m, 1H), 0.55-0.45 (m, 1H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.80 388.1270 IR 3332, 1257, 1211, 1165 74 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 8.58 (d, J = m/z 418 1.6 Hz, 1H), 8.45 (s, 2H), 7.84 (dd, J = 8.3, 2.3 Hz, 1H), [M + H]⁺ 7.57-7.53 (m, 2H), 7.51 (dd, J = 8.3, 0.8 Hz, 1H), 7.34- 7.29 (m, 2H), 5.58 (s, 1H), 3.38-3.25 (m, 2H), 1.05 (s, 9H) ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 75 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.88 (dd, J = 2.5, 0.9 Hz, (m/z) 1H), 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 8.28 (dd, J = 2.7, 0.8 [M + H]⁺ Hz, 1H), 7.98 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.66-7.56 calcd for (m, 2H), 7.47 (dd, J = 8.7, 0.8 Hz, 1H), 7.36 (dd, J = 8.7, C₂₁H₂₀F₃N₂O₂, 2.7 Hz, 1H), 7.30-7.21 (m, 1H), 7.09-7.02 (m, 2H), 389.1471; 5.67 (s, 1H), 2.90-2.75 (m, 1H), 0.95 (d, J = 6.7 Hz, 3H), found, 0.79 (d, J = 6.6 Hz, 3H) 389.1479 ¹⁹F NMR (376 MHz, CDCl₃) δ −61.97 IR 1472, 1325, 1242 76 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.80 (dd, J = 2.4, 0.9 Hz, (m/z) 1H), 8.51 (dd, J = 4.8, 1.6 Hz, 1H), 8.32 (dd, J = 2.6, 0.9 [M + H]⁺ Hz, 1H), 7.88 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.69-7.57 calcd for (m, 2H), 7.37 (dd, J = 8.6, 2.6 Hz, 1H), 7.33 (dd, J = 8.6, C₂₁H₁₈F₃N₂O₂, 0.9 Hz, 1H), 7.31-7.23 (m, 1H), 7.17-7.04 (m, 2H), 387.1315; 5.44 (s, 1H), 1.66 (tt, J = 8.1, 5.3 Hz, 1H), 0.75-0.60 (m, found, 2H), 0.58-0.50 (m, 1H), 0.50-0.41 (m, 1H) 387.1320 ¹⁹F NMR (376 MHz, CDCl₃) δ −61.96 IR 1473, 1323, 1242, 1065 77 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.90 (dd, J = 2.5, 0.9 Hz, (m/z) 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 8.36 (dd, J = 2.5, 0.9 [M + H]⁺ Hz, 1H), 8.06 (dd, J = 2.7, 0.7 Hz, 1H), 7.99 (ddd, J = 8.0, calcd for 2.4, 1.6 Hz, 1H), 7.68 (dd, J = 8.7, 2.7 Hz, 1H), 7.33- C₁₉H₁₉ClN₃O₂, 7.15 (m, 1H), 7.57-7.41 (m, 2H), 6.94 (dd, J = 8.7, 0.7 356.1160; Hz, 1H), 5.80 (s, 1H), 2.83 (hept, J = 6.9 Hz, 1H), 0.95 (d, found, J = 6.7 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H) 356.1165 IR 3344, 1457, 1370, 1270 78 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.85 (dd, J = 2.3, 0.9 Hz, (m/z) 1H), 8.71 (dd, J = 2.3, 0.9 Hz, 1H), 8.52 (dd, J = 4.8, 1.7 [M + H]⁺ Hz, 1H), 7.89 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 7.85 (dd, J = calcd for 8.2, 2.3 Hz, 1H), 7.63-7.54 (m, 2H), 7.38 (dd, J = 8.2, C₂₁H₁₈F₃N₂O₂, 0.9 Hz, 1H), 7.31-7.22 (m, 1H), 7.34 (dq, J = 8.8, 0.9 387.1315; Hz, 2H), 5.70 (s, 1H), 1.70 (tt, J = 8.2, 5.3 Hz, 1H), 0.76- found, 0.62 (m, 2H), 0.56 (dtd, J = 9.6, 5.5, 4.3 Hz, 1H), 0.46 387.1324 (dddd, J = 9.1, 8.2, 6.1, 4.3 Hz, 1H) ¹⁹F NMR (376 MHz, CDCl₃) δ −57.81 IR 1257, 1210, 1165 79 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.84 (dd, J = 2.4, 0.9 Hz, (m/z) 1H), 8.51 (dd, J = 4.8, 1.7 Hz, 1H), 8.39 (dd, J = 2.6, 0.7 [M + H]⁺ Hz, 1H), 8.09 (dd, J = 2.7, 0.7 Hz, 1H), 7.87 (ddd, J = 8.0, calcd for 2.4, 1.6 Hz, 1H), 7.70 (dd, J = 8.7, 2.7 Hz, 1H), 7.52 (dd, C₁₉H₁₇ClN₃O₂, J = 8.6, 2.6 Hz, 1H), 7.31-7.22 (m, 1H), 7.34 (dd, J = 354.1004; 8.6, 0.8 Hz, 1H), 6.98 (dd, J = 8.7, 0.7 Hz, 1H) 5.55 (s, found, 1H), 1.67 (tt, J = 8.2, 5.3 Hz, 1H), 0.73-0.60 (m, 2H), 354.1004 0.60-0.51 (m, 1H), 0.50-0.40 (m, 1H) IR 1457, 1370, 1269 80 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.03 (d, J = 2.4 Hz, 1H), (m/z) 8.73 (dd, J = 2.2, 1.1 Hz, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, [M + H]⁺ 1H), 8.17 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.99-7.84 (m, calcd for 2H), 7.67-7.56 (m, 2H), 7.40-7.30 (m, 2H), 7.31-7.17 C₂₂H₂₂F₃N₂O₂, (m, 1H), 6.26 (s, 1H), 1.10 (s, 9H) 403.1628; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.81 found, IR3197, 1256, 1210,1166 403.1632 81 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.90-8.80 (m, 1H), 8.71 (m/z) (dd, J = 2.3, 0.9 Hz, 1H), 8.51 (dd, J = 4.7, 1.7 Hz, 1H), [M + H]⁺ 7.89 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.84 (dd, J = 8.2, 2.3 calcd for Hz, 1H), 7.63-7.53 (m, 2H), 7.36 (dd, J = 8.3, 0.9 Hz, C₂₁H¹⁹F₂N₂O₂, 1H), 7.31-7.19 (m, 3H), 6.57 (t, J = 73.5 Hz, 1H), 5.72 369.1409; (s, 1H), 1.70 (tt, J = 8.3, 5.3 Hz, 1H), 0.76-0.61 (m, 2H), found, 0.61-0.50 (m, 1H), 0.50-0.40 (m, 1H) 369.1414 ¹⁹F NMR (376 MHz, CDCl₃) δ −81.04 IR 3335, 1475, 1220, 1124, 1043 82 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.03 (dd, J = 2.5, 0.9 Hz, (m/z) 1H), 8.73 (dd, J = 2.2, 1.1 Hz, 1H), 8.46 (dd, J = 4.7, 1.6 [M + H]⁺ Hz, 1H), 8.17 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.95-7.84 calcd for (m, 2H), 7.64-7.53 (m, 2H), 7.34-7.19 (m, 3H), 6.57 (t, C₂₂H₂₃F₂N₂O₂, J = 73.6 Hz, 1H), 6.31 (s, 1H), 1.10 (s, 9H) 385.1722; ¹⁹F NMR (376 MHz, CDCl₃) δ −81.03 found, IR 3255, 1475, 1219, 1126, 1049 385.1734 83 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 2H), 8.75 (dd, J = (m/z) 2.3, 0.9 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, 1H), 7.82 (dd, [M + H]⁺ J = 8.4, 1.0 Hz, 1H), 7.65-7.56 (m, 2H), 7.39-7.31 (m, calcd for 2H), 6.14 (s, 1H), 2.71 (s, 3H), 1.08 (s, 9H) C₂₂H₂₃F₃N₃O₂, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.81 418.1737; IR 3279, 1257, 1211, 1167 found, 418.1741 84 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.73 (dd, J = 2.3, 0.9 Hz, m/z 409 1H), 8.70 (s, 1H), 8.13 (d, J = 0.7 Hz, 1H), 7.89 (dd, J = [M + H]⁺ 8.3, 2.3 Hz, 1H), 7.74 (dd, J = 8.4, 0.9 Hz, 1H), 7.64- 7.54 (m, 2H), 7.38-7.31 (m, 2H), 6.66 (s, 1H), 1.06 (s, 9H) ¹⁹F NMR (376 MHz, CDCl₃) δ −57.81 85 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.68 (dd, J = 2.3, 0.9 Hz, m/z 377 1H), 8.67 (d, J = 0.7 Hz, 1H), 7.92 (d, J = 0.7 Hz, 1H), [M + H]⁺ 7.88 (dd, J = 8.3, 2.3 Hz, 1H), 7.59-7.51 (m, 3H), 7.25- 7.21 (m, 2H), 6.59 (t, J = 72 Hz, 1H), 6.49 (s, 1H), 2.64 (hept, J = 6.7 Hz, 1H), 1.08 (d, J = 6.7 Hz, 3H), 0.72 (d, J = 6.6 Hz, 3H) ¹⁹F NMR (376 MHz, CDCl₃) δ −81.05; 86 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.72 (dd, J = 2.3, 0.9 Hz, m/z 391 1H), 8.69 (d, J = 0.6 Hz, 1H), 8.12 (d, J = 0.7 Hz, 1H), [M + H]⁺ 7.88 (dd, J = 8.3, 2.3 Hz, 1H), 7.73 (dd, J = 8.4, 0.9 Hz, 1H), 7.61-7.54 (m, 2H), 7.26-7.21 (m, 2H), 6.71 (s, 1H), 6.57 (t, J = 72 Hz, 1H), 1.06 (s, 9H) ¹⁹F NMR (376 MHz, CDCl₃) δ −81.0 87 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.69 (dd, J = 2.3, 0.9 Hz, m/z 395 1H), 8.67 (d, J = 0.7 Hz, 1H), 7.92 (d, J = 0.7 Hz, 1H), [M + H]⁺ 7.89 (dd, J = 8.3, 2.3 Hz, 1H), 7.61-7.54 (m, 3H), 7.33 (ddt, J = 7.8, 2.1, 1.1 Hz, 2H), 6.38 (s, 1H), 2.65 (hept., J = 6.7 Hz, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.72 (d, J = 6.6 Hz, 3H) ¹⁹F NMR (376 MHz, CDCl₃) δ −57.81 88 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.81 (dd, J = 2.4, 0.9 Hz, 1H), 7.98 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.90 (dd, J = 8.4, 1.0 Hz, 1H), 7.84-7.75 (m, 2H), calcd for 7.74-7.66 (m, 2H), 5.94 (s, 1H), 1.09 (s, 9H) C₂₁H₂₁N₄O, IR 3246, 2228, 1410 345.1710; found, 345.1713 89 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.74 (d, J = 0.7 Hz, 1H), m/z 393 8.72 (dd, J = 2.3, 0.9 Hz, 1H), 7.92-7.88 (m, 2H), 7.63- [M + H]⁺ 7.58 (m, 2H), 7.50 (dd, J = 8.2, 0.9 Hz, 1H), 7.34 (dq, J = 7.7, 1.1 Hz, 2H), 5.98 (s, 1H), 1.77-1.65 (m, 1H), 0.83 (dddd, J = 9.5, 6.0, 5.2, 4.3 Hz, 1H), 0.71-0.62 (m, 1H), 0.56 (dddd, J = 9.6, 5.9, 5.1, 4.3 Hz, 1H), 0.48-0.38 (m, 1H) ¹⁹F NMR (376 MHz, CDCl₃) δ −57.80 90 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.97 (s, 2H), (m/z) 8.67 (dd, J = 2.3, 0.9 Hz, 1H), 7.91 (dd, J = 8.3, 2.3 Hz, [M + H]⁺ 1H), 7.65-7.55 (m, 3H), 7.39-7.29 (m, 2H), 7.23 (t, J = calcd for 8.1 Hz, 1H), 7.04-6.96 (m, 1H), 6.92 (dd, J = 9.8, 2.1 C₂₄H₁₇ClF₄N₃O₂, Hz, 1H), 5.66 (d, J = 0.6 Hz, 1H), 3.80-3.52 (m, 2H) 490.0940; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82, −114.06 found, IR 3242, 1489, 1410, 1257 490.0939 91 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H), 8.81 (dd, J = (m/z) 2.4, 0.9 Hz, 1H), 8.71 (d, J = 0.5 Hz, 2H), 7.91 (dd, J = [M + H]⁺ 8.2, 2.3 Hz, 1H), 7.69-7.57 (m, 2H), 7.48-7.32 (m, calcd for 4H), 6.92 (tdd, J = 8.8, 2.6, 1.0 Hz, 1H), 6.85 (ddd, J = C₂₂H₁₅F₅N₃O₂, 11.2, 8.5, 2.5 Hz, 1H), 6.21 (d, J = 0.6 Hz, 1H) 460.1079; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.80, −103.26 (d, J = 8.9 found, Hz), −108.91 (d, J = 9.0 Hz) 460.1080 IR 3159, 1256, 1211, 1167 92 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.09 (s, 1H), m/z 419 8.74 (dd, J = 2.3, 0.9 Hz, 1H), 8.37 (dd, J = 2.5, 0.7 Hz, [M + H]⁺; 1H), 7.92 (dd, J = 8.4, 2.3 Hz, 1H), 7.86 (dt, J = 8.6, 1.7 m/z 417 Hz, 2H), 7.00 (dd, J = 8.6, 0.7 Hz, 1H), 6.09 (s, 1H), 4.82 [M − H]⁻ (q, J = 8.5 Hz, 2H), 1.09 (s, 9H) ¹⁹F NMR (376 MHz, CDCl₃) δ −73.79 93 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.76 (dd, J = 2.4, 0.9 Hz, 1H), 7.94 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.86 (dd, J = 8.4, 1.0 Hz, 1H), 7.66-7.56 (m, 2H), calcd for 7.35 (dd, J = 8.4, 1.3 Hz, 2H), 6.20 (s, 1H), 1.59-1.45 C₂₂H₂3F₃N₃O₂, (m, 1H), 1.45-1.32 (m, 1H), 1.04 (s, 6H), 0.82 (t, J = 7.5 418.1737; Hz, 3H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.80 418.1738 94 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.83 (d, J = 0.7 Hz, 1H), (m/z) 8.77 (dd, J = 2.3, 0.9 Hz, 1H), 7.90 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.66-7.56 (m, 3H), 7.45-7.38 (m, 2H), 7.38-7.32 calcd for (m, 2H), 6.92-6.85 (m, 1H), 6.81 (ddd, J = 11.2, 8.6, 2.6 C₂₂H₁₄F₅N₂O₂S, Hz, 1H), 6.46 (d, J = 0.6 Hz, 1H) 465.0691; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.80, −103.95 (d, J = 9.1 found, Hz), −109.30 (d, J = 9.0 Hz) 465.0688 95 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 2H), 9.08 (s, 1H), (m/z) 8.74 (dd, J = 2.4, 0.9 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.81 (dd, J = 8.4, 0.9 Hz, 1H), 7.60-7.46 (m, 2H), calcd for 7.10-6.98 (m, 2H), 6.40 (s, 1H), 3.87 (s, 3H), 1.08 (s, C₂₁H₂₄N₃O₂, 9H) 350.1863; found, 350.1869 96 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.81 (dd, J = 2.4, 0.9 Hz, 1H), 7.98 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.88 (dd, J = 8.3, 0.9 Hz, 1H), 7.78-7.74 (m, 2H), calcd for 7.72-7.65 (m, 2H), 6.07 (s, 1H), 1.09 (s, 9H) C₂₁H₂₁F₃N₃O, ¹⁹F NMR (376 MHz, CDCl₃) δ −62.63 388.1631; found, 388.1636 97 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.77 (dd, J = 2.3, 0.9 Hz, 1H), 7.96 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.82 (dd, J = 8.4, 0.9 Hz, 1H), 7.52 (s, 4H), 6.39 (s, calcd for 1H), 1.37 (s, 9H), 1.08 (s, 9H) C₂₄H₃₀N₃O, 376.2383; found, 376.2382 98 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.76 (dd, J = 2.3, 0.9 Hz, 1H), 7.94 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.82 (dd, J = 8.3, 0.9 Hz, 1H), 7.59-7.46 (m, 2H), calcd for 7.41-7.31 (m, 2H), 6.30 (s, 1H), 2.54 (s, 3H), 1.08 (s, C₂₁H₂₄N₃OS, 9H) 366.1635; found, 366.1637 99 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.90 (s, 2H), (m/z) 8.75 (dd, J = 2.4, 0.9 Hz, 1H), 7.89 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.64-7.54 (m, 2H), 7.43 (dd, J = 8.2, 0.9 Hz, 1H), calcd for 7.38-7.30 (m, 2H), 5.72 (s, 1H), 2.01 (s, 3H) C₁₈H₁₅F₃N₃O₂, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.81 362.1111; found, 362.1114 100 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 2H), 9.07 (s, 1H), (m/z) 8.73 (dd, J = 2.4, 0.9 Hz, 1H), 7.91 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.77 (dd, J = 8.4, 0.9 Hz, 1H), 7.59-7.45 (m, 2H), calcd for 6.88-6.76 (m, 2H), 6.53 (s, 1H), 3.02 (s, 6H), 1.07 (s, C₂₂H₂₇N₄O, 9H) 363.2179; found, 363.2182 101 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.83 (dd, J = 2.3, 0.9 Hz, 1H), 8.15-8.04 (m, 2H), 8.01 [M + H]⁺ (dd, J = 8.4, 2.4 Hz, 1H), 7.88 (dd, J = 8.4, 0.9 Hz, 1H), calcd for 7.77-7.63 (m, 2H), 6.11 (s, 1H), 2.66 (s, 3H), 1.09 (s, C₂₂H₂₄N₃O₂, 9H) 362.1863; found, 362.1866 102 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 2H), 9.08 (s, 1H), (m/z) 8.74 (dd, J = 2.4, 0.9 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.81 (dd, J = 8.4, 0.9 Hz, 1H), 7.56-7.47 (m, 2H), calcd for 7.20-7.13 (m, 2H), 6.40 (s, 1H), 3.88-3.58 (m, 1H), C₂₃H₂₆N₃O₂, 1.08 (s, 9H), 0.91-0.73 (m, 4H) 376.2020; found, 376.2019 103 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.78 (dd, J = 2.4, 0.9 Hz, 1H), 7.96 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.87 (dd, J = 8.4, 0.9 Hz, 1H), 7.58-7.48 (m, 2H), calcd for 7.43 (td, J = 1.9, 1.0 Hz, 1H), 7.29 (ddd, J = 6.5, 2.4, 1.3 C₂₁H₂₁F₃N₃O₂, Hz, 1H), 6.11 (s, 1H), 1.09 (s, 9H) 404.1580; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.74 found, 404.1583 104 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 2H), 9.10 (s, 1H), (m/z) 8.66 (dd, J = 2.3, 1.0 Hz, 1H), 7.90 (dd, J = 8.4, 2.2 Hz, [M + H]⁺ 1H), 7.85 (dd, J = 8.3, 1.0 Hz, 1H), 7.53-7.36 (m, 4H), calcd for 6.22 (s, 1H), 1.08 (s, 9H) C₂₁H₂₁F₃N₃O₂, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.20 404.1580; found, 404.1582 105 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.76 (dd, J = 2.4, 0.9 Hz, 1H), 7.95 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.85 (dd, J = 8.4, 0.9 Hz, 1H), 7.61-7.54 (m, 2H), calcd for 7.46-7.38 (m, 2H), 6.21 (s, 1H), 1.85-1.76 (m, 2H), C₂₄H₂₅N₄O, 1.50-1.43 (m, 2H), 1.08 (s, 9H) 385.2023; found, 385.2026 106 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.76 (dd, J = 2.3, 0.9 Hz, 1H), 7.93 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.87 (dd, J = 8.4, 1.0 Hz, 1H), 7.49-7.34 (m, 3H), calcd for 5.99 (s, 1H), 1.08 (s, 9H) C₂₁H₂₀F₄N₃O₂, ¹⁹F NMR (376 MHz, CDCl₃) δ −58.71 (d, J = 4.8 422.1486; Hz), −127.10 (q, J = 4.8 Hz) found, 422.1490 107 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 2H), 9.10 (s, 1H), (m/z) 8.97 (d, J = 2.3 Hz, 1H), 8.84 (dd, J = 2.4, 1.0 Hz, 1H), [M + H]⁺ 8.07 (dd, J = 7.9, 2.3 Hz, 1H), 8.01 (dd, J = 8.4, 2.4 Hz, calcd for 1H), 7.94 (dd, J = 8.4, 1.0 Hz, 1H), 7.86-7.81 (m, 1H), C₂₀H₂₀F₃N₄O, 5.78 (s, 1H), 1.10 (s, 9H) 389.1584; ¹⁹F NMR (376 MHz, CDCl₃) δ −67.88 found, 389.1592 108 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 2H), 9.10 (s, 1H), (m/z) 8.97 (dd, J = 2.3, 0.9 Hz, 1H), 8.84 (dd, J = 2.4, 1.0 Hz, [M + H]⁺ 1H), 8.03 (dd, J = 13.6, 2.4 Hz, 1H), 8.01 (dd, J = 14.0, calcd for 2.3 Hz, 1H), 7.95 (dd, J = 8.4, 1.0 Hz, 1H), 7.84 (dd, J = C₂₀H₂₀N₅O, 8.1, 0.9 Hz, 1H), 5.64 (s, 1H), 1.10 (s, 9H) 346.1662; found, 346.1664 109 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.79 (dd, J = 2.4, 0.9 Hz, 1H), 7.97 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.84 (dd, J = 8.4, 0.9 Hz, 1H), 7.66-7.45 (m, 4H), calcd for 6.77 (dd, J = 17.6, 10.9 Hz, 1H), 6.31 (s, 1H), 5.83 (dd, C₂₂H₂₄N₃O, J = 17.6, 0.8 Hz, 1H), 5.33 (dd, J = 10.9, 0.8 Hz, 1H), 1.09 346.1914; (s, 9H) found, 346.1917 110 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 2H), 9.08 (s, 1H), (m/z) 8.80 (dd, J = 2.3, 0.9 Hz, 1H), 7.96 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.80 (dd, J = 8.4, 0.9 Hz, 1H), 7.55 (dd, J = 2.9, 1.3 calcd for Hz, 1H), 7.47 (dd, J = 5.0, 2.9 Hz, 1H), 7.40 (dd, J = 5.0, C₁₈H₂₀N₃OS, 1.4 Hz, 1H), 6.26 (s, 1H), 1.07 (s, 9H) 326.1322; found, 326.1328 111 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.78 (dd, J = 2.4, 0.9 Hz, 1H), 7.97 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.84 (dd, J = 8.4, 0.9 Hz, 1H), 7.62-7.55 (m, 2H), calcd for 7.50-7.42 (m, 2H), 6.32 (s, 1H), 4.52 (s, 2H), 3.44 (s, C₂₂H₂₆N₃O₂, 3H), 1.08 (s, 9H) 364.2020; found, 364.2024 112 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.78 (dt, J = 2.3, 1.1 Hz, 1H), 8.29 (ddd, J = 4.9, 2.0, 1.2 [M + H]⁺ Hz, 1H), 8.01 (ddd, J = 8.4, 2.3, 1.6 Hz, 1H), 7.98-7.85 calcd for (m, 2H), 7.36 (ddd, J = 7.4, 4.9, 1.7 Hz, 1H), 5.99 (s, 1H), C₁₉H₂₀FN₄O, 1.09 (s, 9H) 339.1616; ¹⁹F NMR (376 MHz, CDCl₃) δ −70.55 found, 339.1616 113 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.30 (s, 1H), 9.23 (s, 2H), (m/z) 9.10 (s, 1H), 8.99 (s, 2H), 8.83 (dd, J = 2.3, 1.0 Hz, 1H), [M + H]⁺ 7.99 (dd, J = 8.4, 2.3 Hz, 1H), 7.95 (dd, J = 8.4, 1.0 Hz, calcd for 1H), 5.73 (s, 1H), 1.10 (s, 9H) C₁₈H₂₀N₅O, 322.1662; found, 322.1663 114 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.78 (dd, J = 2.4, 0.9 Hz, 1H), 7.97 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.84 (dd, J = 8.4, 0.9 Hz, 1H), 7.62-7.55 (m, 2H), calcd for 7.53-7.46 (m, 2H), 7.46-7.40 (m, 1H), 6.33 (s, 1H), C₂₀H₂₂N₃O, 1.09 (s, 9H) 320.1757; found, 320.1755 115 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.74 (dd, J = 2.4, 0.9 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.84 (dd, J = 8.4, 1.0 Hz, 1H), 7.61-7.48 (m, 2H), calcd for 7.23-7.13 (m, 2H), 6.23 (s, 1H), 1.08 (s, 9H) C₂₀H₂₁FN₃O, ¹⁹F NMR (376 MHz, CDCl₃) δ −113.43 338.1663; found, 338.1668 116 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.75 (dd, J = 2.3, 0.9 Hz, 1H), 7.93 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.84 (dd, J = 8.4, 0.9 Hz, 1H), 7.46 (dd, J = 1.9, 1.2 calcd for Hz, 1H), 7.41 (ddd, J = 8.5, 2.3, 0.7 Hz, 1H), 7.35-7.29 C₂₂H₂₃F₃N₃O₂, (m, 1H), 6.20 (s, 1H), 2.40 (s, 3H), 1.08 (s, 9H) 418.1737; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.42 found, 418.1742 117 HRMS-ESI (m/z) ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 2H), 9.10 (s, 1H), [M + H]⁺ 8.52 (dd, J = 2.3, 0.9 Hz, 1H), 7.85 (dd, J = 8.3, 1.0 Hz, calcd for 1H), 7.73 (dd, J = 8.3, 2.3 Hz, 1H), 7.23 (d, J = 8.3 Hz, C₂₂H₂₃F₃N₃O₂, 1H), 7.20-7.10 (m, 2H), 6.24 (s, 1H), 2.27 (s, 3H), 1.09 418.1737; (s, 9H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.69 418.1740 118 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.25 (s, 1H), 8.96 (s, 1H), (m/z) 8.81 (dd, J = 2.3, 0.9 Hz, 1H), 7.80 (dd, J = 8.3, 2.4 Hz, [M + H]⁺ 1H), 7.66-7.58 (m, 2H), 7.41-7.31 (m, 2H), 7.10 (dd, calcd for J = 8.2, 0.9 Hz, 1H), 5.92 (s, 1H), 2.13 (s, 3H), 1.23 (s, 9H) C₂₂H₂₃F₃N₃O₂, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 418.1737; found, 418.1737 119 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.09 (s, 1H), (m/z) 8.36 (s, 1H), 7.70-7.63 (m, 1H), 7.40-7.28 (m, 4H), [M + H]⁺ 6.31 (s, 1H), 2.36 (d, J = 0.6 Hz, 3H), 1.09 (s, 9H) calcd for ¹⁹F NMR (376 MHz, CDCl₃) δ −57.78 C₂₂H₂₃F₃N₃O₂, 418.1737; found, 418.1739 120 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.74 (dd, J = 2.4, 0.9 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.82 (dd, J = 8.3, 0.9 Hz, 1H), 7.60-7.49 (m, 2H), calcd for 7.14-7.03 (m, 2H), 6.28 (s, 1H), 4.41 (q, J = 8.1 Hz, 2H), C₂₂H₂₃F₃N₃O₂, 1.08 (s, 9H) 418.1737; ¹⁹F NMR (376 MHz, CDCl₃) δ −73.87 found, 418.1736 121 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.78 (dd, J = 2.3, 0.9 Hz, 1H), 7.97 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.84 (dd, J = 8.4, 1.0 Hz, 1H), 7.68-7.62 (m, 2H), calcd for 7.61-7.53 (m, 2H), 6.33 (s, 1H), 1.09 (s, 9H), 0.31 (s, C₂₃H₃₀N₃OSi, 9H) 392.2153; found, 392.2155 122 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 2H), 9.07 (s, 1H), (m/z) 8.68 (dd, J = 2.3, 0.9 Hz, 1H), 7.82 (dd, J = 8.3, 2.3 Hz, [M + H]⁺ 1H), 7.79 (d, J = 0.8 Hz, 1H), 7.75 (dd, J = 8.4, 1.0 Hz, calcd for 1H), 7.68 (d, J = 0.8 Hz, 1H), 6.27 (s, 1H), 3.98 (s, 3H), C₁₈H₂₂N₅O, 1.06 (s, 9H) 324.1819; found, 324.1823 123 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 2H), 9.08 (s, 1H), (m/z) 8.70 (dd, J = 2.3, 1.0 Hz, 1H), 7.85 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.80 (dd, J = 1.5, 0.9 Hz, 1H), 7.77 (dd, J = 8.4, 1.0 calcd for Hz, 1H), 7.56-7.52 (m, 1H), 6.72 (dd, J = 1.9, 0.9 Hz, C₁₈H₂₀N₃O₂, 1H), 6.22 (s, 1H), 1.06 (s, 9H) 310.1550; found, 310.1549 124 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.72 (ddd, J = 2.3, 1.4, 0.9 Hz, 1H), 7.95 (ddd, J = 8.4, [M + H]⁺ 2.3, 1.5 Hz, 1H), 7.87 (dd, J = 8.4, 1.0 Hz, 1H), 7.48 (t, calcd for J = 8.5 Hz, 1H), 7.24-7.07 (m, 2H), 6.09 (s, 1H), 1.09 (s, C₂₁H₂₀F₄N₃O₂, 9H) 422.1486; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.97, −113.27 found, 422.1486 125 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.80 (dd, J = 2.4, 1.0 Hz, 1H), 7.98 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.87 (dd, J = 8.4, 1.0 Hz, 1H), 7.82-7.75 (m, 2H), calcd for 7.70-7.58 (m, 2H), 6.09 (s, 1H), 1.09 (s, 9H) C₂₁H₂₁F₃N₃OS, ¹⁹F NMR (376 MHz, CDCl₃) δ −42.46 420.1352; found, 420.1355 126 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.87 (dd, J = 2.4, 0.9 Hz, 1H), 8.80 (dd, J = 2.4, 1.0 Hz, [M + H]⁺ 1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 7.98 (dd, J = 8.4, 2.3 calcd for Hz, 1H), 7.92-7.87 (m, 2H), 7.44 (ddd, J = 7.9, 4.8, 0.9 C₁₉H₂₁N₄O, Hz, 1H), 6.05 (s, 1H), 1.09 (s, 9H) 321.1710; found, 321.1710 127 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 2H), 9.17 (d, J = (m/z) 2.3 Hz, 1H), 9.10 (s, 1H), 8.94 (dd, J = 2.4, 0.9 Hz, 1H), [M + H]⁺ 8.41-8.30 (m, 1H), 8.25-8.14 (m, 1H), 8.12 (dd, J = calcd for 8.3, 2.4 Hz, 1H), 8.03-7.85 (m, 2H), 7.79 (ddd, J = 8.5, C₂₃H₂₃N₄O, 6.9, 1.5 Hz, 1H), 7.64 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 6.07 371.1866; (s, 1H), 1.11 (s, 9H) found, 371.1861 128 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 2H), 9.11 (s, 1H), (m/z) 8.54 (d, J = 2.2 Hz, 1H), 8.06 (s, 1H), 7.90 (d, J = 8.2 Hz, [M + H]⁺ 1H), 7.87 (dd, J = 8.3, 1.0 Hz, 1H), 7.81-7.71 (m, 1H), calcd for 7.50 (d, J = 8.0 Hz, 1H), 5.93 (s, 1H), 1.08 (s, 9H) C₂₂H₂₀F₆N₃O, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.27, −62.92 456.1505; found, 456.1509 130 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.80 (dd, J = 2.4, 0.9 Hz, 1H), 7.98 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.84 (dd, J = 8.4, 1.0 Hz, 1H), 7.82-7.73 (m, 2H), calcd for 7.65-7.55 (m, 2H), 6.27 (s, 1H), 4.03 (s, 3H), 2.26 (s, C₂₃H₂₇N₄O₂, 3H), 1.09 (s, 9H) 391.2129; found, 391.2132 131 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.81 (s, 2H), (m/z) 8.65 (dd, J = 2.4, 0.7 Hz, 1H), 7.65-7.57 (m, 2H), 7.56 [M + H]⁺ (dd, J = 2.4, 0.7 Hz, 1H), 7.34 (dq, J = 8.8, 1.0 Hz, 2H), calcd for 4.38 (s, 1H), 1.98 (d, J = 0.6 Hz, 3H), 1.26 (s, 9H) C₂₂H₂₃F₃N₃O₂, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.80 418.1737; found, 418.1743 132 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.79 (dd, J = 2.4, 0.9 Hz, 1H), 7.97 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.85 (dd, J = 8.4, 1.0 Hz, 1H), 7.67-7.56 (m, 4H), calcd for 6.24 (s, 1H), 3.89 (s, 3H), 2.25 (s, 3H), 1.09 (s, 9H) C₂₃H₂₇N₄O₂, 391.2129; found, 391.2128 133 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.09 (s, 1H), (m/z) 8.84 (dd, J = 2.4, 0.9 Hz, 1H), 7.97 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.83 (dd, J = 8.4, 0.9 Hz, 1H), 7.52 (d, J = 3.9 Hz, calcd for 1H), 7.36 (d, J = 3.9 Hz, 1H), 5.85 (s, 1H), 5.73 (s, 2H), C₁₉H₂₁N₄O₂S, 1.08 (s, 9H) 369.1380; ¹³C NMR (126 MHz, CDCl₃) δ 163.02, 160.48, 156.92, found, 156.39, 144.69, 144.33, 138.23, 136.88, 133.96, 130.07, 369.1377 128.68, 124.98, 122.40, 79.63, 40.18, 26.25 134 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 2H), 9.08 (s, 1H), (m/z) 8.82 (dd, J = 2.4, 0.9 Hz, 1H), 7.95 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.78 (dd, J = 8.4, 0.9 Hz, 1H), 7.46-7.35 (m, 2H), calcd for 7.23-7.09 (m, 1H), 6.11 (s, 1H), 1.07 (s, 9H) C₁₈H₂₀N₃OS, 326.1322; found, 326.1327 135 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 9.01 (s, 2H), (m/z) 8.71 (dd, J = 2.3, 0.9 Hz, 1H), 7.88 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.63-7.54 (m, 3H), 7.38-7.30 (m, 2H), 7.21-7.15 calcd for (m, 3H), 7.06-7.00 (m, 2H), 4.99 (s, 1H), 3.79 (d, J = C₂₄H₁₉F₃N₃O₂, 13.6 Hz, 1H), 3.58 (d, J = 13.5 Hz, 1H) 438.1424; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 found, 438.1425 136 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.98 (s, 2H), (m/z) 8.69 (dd, J = 2.3, 0.9 Hz, 1H), 7.90 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.60-7.56 (m, 2H), 7.54 (dd, J = 8.2, 0.9 Hz, 1H), calcd for 7.38-7.31 (m, 2H), 7.06-6.97 (m, 2H), 6.91-6.81 (m, C₂₄H₁₈F₄N₃O₂, 2H), 5.24 (s, 1H), 3.73 (d, J = 13.7 Hz, 1H), 3.55 (d, J = 456.1330; 13.7 Hz, 1H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82, −115.64 456.1332 137 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 2H), 9.07 (s, 1H), (m/z) 8.72 (dd, J = 2.4, 0.9 Hz, 1H), 7.90 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.79 (dd, J = 8.4, 0.9 Hz, 1H), 7.31 (dd, J = 8.4, 2.4 calcd for Hz, 1H), 7.29-7.23 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H), C₂₃H₂₆N₃O₂, 6.42 (s, 1H), 4.41-4.06 (m, 2H), 2.86 (t, J = 6.5 Hz, 2H), 376.2020; 2.17-1.88 (m, 2H), 1.07 (s, 9H) found, 376.2020 138 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.97 (s, 2H), (m/z) 8.67 (dd, J = 2.3, 0.9 Hz, 1H), 7.91 (dd, J = 8.3, 2.3 Hz, [M + H]⁺ 1H), 7.63-7.54 (m, 3H), 7.34 (dq, J = 8.6, 0.9 Hz, 2H), calcd for 7.25 (s, 1H), 6.78-6.70 (m, 1H), 6.64 (ddd, J = 10.2, 8.9, C₂₄H₁₇F₅N₃O₂, 2.6 Hz, 1H), 5.63 (d, J = 0.6 Hz, 1H), 3.85-3.45 (m, 2H) 474.1235; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82, −111.42 (d, J = 7.5 found, Hz), −112.47 (d, J = 7.5 Hz) 474.1237 139 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.99 (s, 2H), (m/z) 8.70 (dd, J = 2.3, 0.9 Hz, 1H), 7.90 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.59-7.56 (m, 2H), 7.55 (dd, J = 8.3, 0.9 Hz, 1H), calcd for 7.39-7.31 (m, 2H), 7.13 (td, J = 8.1, 6.1 Hz, 1H), 6.91- C₂₄H₁₈F₄N₃O₂, 6.84 (m, 1H), 6.84-6.78 (m, 2H), 5.29 (s, 1H), 3.75 (d, 456.1330; J = 13.7 Hz, 1H), 3.57 (d, J = 13.6 Hz, 1H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82, −113.32 456.1329 140 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.98 (s, 2H), (m/z) 8.69 (dd, J = 2.3, 0.9 Hz, 1H), 7.90 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.61-7.55 (m, 2H), 7.54 (dd, J = 8.2, 0.9 Hz, 1H), calcd for 7.38-7.31 (m, 2H), 7.17-7.10 (m, 2H), 7.03-6.94 (m, C₂₄H₁₈ClF₃N₃O₂, 2H), 5.30 (s, 1H), 3.72 (d, J = 13.6 Hz, 1H), 3.54 (d, J = 472.1034; 13.7 Hz, 1H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 472.1009 141 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.99 (s, 2H), (m/z) 8.68 (dd, J = 2.3, 0.9 Hz, 1H), 7.90 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.59-7.55 (m, 2H), 7.53 (dd, J = 8.2, 0.9 Hz, 1H), calcd for 7.34 (dq, J = 8.8, 1.0 Hz, 2H), 7.15 (ddd, J = 8.0, 2.1, 1.2 C₂₄H₁₈ClF₃N₃O₂, Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 1.9 Hz, 1H), 472.1034; 6.92 (dt, J = 7.6, 1.4 Hz, 1H), 5.34 (s, 1H), 3.71 (d, J = found, 13.6 Hz, 1H), 3.54 (d, J = 13.6 Hz, 1H) 472.1013 ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 142 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.92 (s, 2H), (m/z) 8.70 (dd, J = 2.3, 0.9 Hz, 1H), 7.91 (dd, J = 8.2, 2.3 Hz, [M + H]⁺ 1H), 7.65-7.54 (m, 3H), 7.37-7.31 (m, 2H), 7.31-7.26 calcd for (m, 2H), 7.09 (dd, J = 8.4, 2.2 Hz, 1H), 5.58 (s, 1H), 3.87- C₂₄H₁₇Cl₂F₃N₃O₂, 3.76 (m, 2H) 506.0644; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 found, 506.0643 143 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.09-9.01 (m, 1H), 8.74 (m/z) (dd, J = 2.3, 1.0 Hz, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), [M + H]⁺ 8.18 (ddd, J = 8.2, 2.5, 1.6 Hz, 1H), 7.92 (dd, J = 8.4, 2.3 calcd for Hz, 1H), 7.28-7.20 (m, 1H), 7.86 (dd, J = 8.4, 1.0 Hz, C₂₅H₃₁N₂O, 1H), 7.51 (d, J = 0.7 Hz, 4H), 6.46 (s, 1H), 1.37 (s, 9H), 375.2431; 1.09 (s, 9H) found, 375.2435 144 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.82 (d, J = 2.3 Hz, 1H), (m/z) 8.73 (dd, J = 2.2, 1.1 Hz, 1H), 8.29 (dd, J = 2.1, 0.8 Hz, [M + H]⁺ 1H), 7.98 (td, J = 2.2, 0.8 Hz, 1H), 7.90 (dd, J = 8.4, 2.2 calcd for Hz, 1H), 7.87 (dd, J = 8.4, 1.1 Hz, 1H), 7.64-7.55 (m, C₂₃H₂₄F₃N₂O₂, 2H), 7.41-7.29 (m, 2H), 6.30 (s, 1H), 2.33 (q, J = 0.7 Hz, 417.1784; 3H), 1.10 (s, 9H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.81 417.1787 145 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.02 (dd, J = 2.5, 0.9 Hz, (m/z) 1H), 8.74 (dd, J = 2.3, 1.0 Hz, 1H), 8.46 (dd, J = 4.8, 1.6 [M + H]⁺ Hz, 1H), 8.17 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.92 (dd, J = calcd for 8.4, 2.3 Hz, 1H), 7.88 (dd, J = 8.4, 1.0 Hz, 1H), 7.61- C₂₅H₂₆N₃0, 7.54 (m, 2H), 7.46-7.37 (m, 2H), 7.26-7.20 (m, 1H), 384.2070; 6.30 (s, 1H), 1.88-1.73 (m, 2H), 1.50-1.40 (m, 2H), found, 1.10 (s, 9H) 384.2072 146 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.04 (dd, J = 2.5, 0.9 Hz, (m/z) 1H), 8.52-8.44 (m, 2H), 8.21 (ddd, J = 8.1, 2.4, 1.6 Hz, [M + H]⁺ 1H), 7.88 (dd, J = 8.3, 1.0 Hz, 1H), 7.31-7.23 (m, 1H), calcd for 7.69 (dd, J = 8.3, 2.3 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), C₂₃H₂₄F₃N₂O₂, 7.18-7.10 (m, 2H), 6.34 (s, 1H), 2.27 (s, 3H), 1.10 (s, 417.1784; 9H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.69 417.1788 147 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.11-8.98 (m, 1H), 8.69 (m/z) (q, J = 1.5 Hz, 1H), 8.46 (dd, J = 4.7, 1.7 Hz, 1H), 8.17 [M + H]⁺ (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.91 (t, J = 1.5 Hz, 2H), calcd for 7.48 (t, J = 8.5 Hz, 1H), 7.30-7.21 (m, 1H), 7.22-7.04 C₂₂H₂₁F₄N₂O₂, (m, 2H), 6.21 (s, 1H), 1.10 (s, 9H) 421.1534; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.97, −113.28 found, 421.1531 148 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 2.4 Hz, 1H), (m/z) 8.72 (dd, J = 2.3, 1.0 Hz, 1H), 8.04 (dd, J = 8.3, 2.5 Hz, [M + H]⁺ 1H), 7.93-7.79 (m, 2H), 7.69-7.54 (m, 2H), 7.40-7.29 calcd for (m, 2H), 7.10 (d, J = 8.2 Hz, 1H), 6.22 (s, 1H), 2.52 (s, C₂₃H₂₄F₃N₂O₂, 3H), 1.09 (s, 9H) 417.1784; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.81 found, 417.1784 149 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H), 8.78 (dd, J = (m/z) 2.4, 0.9 Hz, 1H), 8.33 (d, J = 4.9 Hz, 1H), 7.76 (dd, J = [M + H]⁺ 8.3, 2.4 Hz, 1H), 7.66-7.56 (m, 2H), 7.38-7.31 (m, calcd for 2H), 7.09 (dd, J = 8.3, 0.9 Hz, 1H), 7.00 (d, J = 4.9 Hz, C₂₃H₂₄F₃N₂O₂, 1H), 5.89 (s, 1H), 1.91 (d, J = 0.6 Hz, 3H), 1.25 (s, 9H) 417.1784; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 found, 417.1787 150 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.13 (dd, J = (m/z) 2.3, 0.9 Hz, 1H), 9.09 (s, 1H), 8.66 (d, J = 2.7 Hz, 1H), [M + H]⁺ 8.40 (dd, J = 8.5, 2.3 Hz, 1H), 7.89 (dd, J = 8.5, 0.9 Hz, calcd for 1H), 7.82 (dd, J = 8.7, 0.7 Hz, 1H), 7.73-7.65 (m, 1H), C₂₀H₂₀F₃N₄O₂, 6.12 (s, 1H), 1.08 (s, 9H) 405.1533; ¹⁹F NMR (376 MHz, CDCl₃) δ −58.11 found, 405.1529 151 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 8.79 (dd, J = 2.4, 0.9 Hz, (m/z) 1H), 8.40 (dd, J = 4.8, 1.6 Hz, 1H), 8.29 (dd, J = 8.2, 1.7 [M + H]⁺ Hz, 1H), 7.74 (dd, J = 8.2, 2.3 Hz, 1H), 7.68-7.57 (m, calcd for 2H), 7.41-7.29 (m, 2H), 7.13 (dd, J = 8.1, 4.7 Hz, 1H), C₂₃H₂₄F₃N₂O₂, 7.03 (dd, J = 8.3, 0.9 Hz, 1H), 5.79 (s, 1H), 2.09 (s, 3H), 417.1784; 1.23 (s, 9H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 417.1786 152 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.78 (dd, J = 2.3, 1.0 Hz, 1H), 7.96 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.85 (dd, J = 8.4, 0.9 Hz, 1H), 7.61 (s, 4H), 6.22 (s, calcd for 1H), 1.78 (s, 6H), 1.09 (s, 9H) C₂₄H₂₇N₄O, 387.2179; found, 387.2179 153 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.78 (dd, J = 2.4, 0.9 Hz, 1H), 7.96 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.86 (dd, J = 8.4, 0.9 Hz, 1H), 7.64-7.55 (m, 2H), calcd for 7.50-7.41 (m, 2H), 6.20 (s, 1H), 3.83 (s, 2H), 1.09 (s, C₂₂H₂₃N₄O, 9H) 359.1866; found, 359.1866 154 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.05 (dd, J = 2.4, 0.9 Hz, (m/z) 1H), 8.73 (t, J = 1.6 Hz, 1H), 8.47 (dd, J = 4.8, 1.6 Hz, [M + H]⁺ 1H), 8.19 (ddd, J = 8.2, 2.5, 1.6 Hz, 1H), 7.93-7.84 (m, calcd for 2H), 7.30-7.21 (m, 1H), 7.62-7.55 (m, 2H), 7.34 (dq, C₂₃H₂₄F₃N₂O₂, J = 8.8, 1.0 Hz, 2H), 6.30 (s, 1H), 1.62-1.47 (m, 1H), 1.47- 417.1782; 1.34 (m, 1H), 1.05 (s, 6H), 0.81 (t, J = 7.5 Hz, 3H) found, ¹⁹F NMR (376 MHz, CDCl₃) δ −57.81 417.1784. 155 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.79 (dd, J = 2.4, 0.9 Hz, 1H), 7.97 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.86 (dd, J = 8.4, 0.9 Hz, 1H), 7.64 (s, 4H), 6.19 (s, calcd for 1H), 1.97 (t, J = 18.1 Hz, 3H), 1.09 (s, 9H) C₂₂H₂₄F₂N₃O, ¹⁹F NMR (376 MHz, CDCl₃) δ −87.73 384.1879; found, 384.1882 156 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.25 (s, 1H), 8.95 (s, 1H), (m/z) 8.55 (dd, J = 2.2, 0.9 Hz, 1H), 7.57 (dd, J = 8.1, 2.2 Hz, [M + H]⁺ 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.20-7.12 (m, 2H), 7.10 calcd for (dd, J = 8.1, 0.9 Hz, 1H), 5.96 (s, 1H), 2.26 (s, 3H), 2.14 C₂₃H₂₅F₃N₃O₂, (s, 3H), 1.24 (s, 9H) 432.1893; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.69 found, 432.1897 157 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 1H), 8.95 (s, 1H), (m/z) 8.76 (ddd, J = 2.3, 1.4, 0.9 Hz, 1H), 7.80 (ddd, J = 8.3, [M + H]⁺ 2.3, 1.5 Hz, 1H), 7.51 (t, J = 8.5 Hz, 1H), 7.17 (ddd, J = calcd for 9.5, 2.1, 1.0 Hz, 1H), 7.15-7.08 (m, 2H), 5.89 (s, 1H), C₂₂H₂₂F₄N₃O₂, 2.14 (s, 3H), 1.23 (s, 9H) 436.1643; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.98, −113.16 found, 436.1645 158 HRMS-ESI ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.51 (dd, J = 2.3, 0.9 Hz, 1H), 7.84 (dd, J = 8.3, 1.0 Hz, [M + H]⁺ 1H), 7.72 (dd, J = 8.3, 2.2 Hz, 1H), 7.30-7.24 (m, 1H), calcd for 7.24-7.12 (m, 2H), 6.29 (s, 1H), 2.27 (s, 3H), 1.84-1.72 C₂₅H₂₇N₄O, (m, 2H), 1.50-1.41 (m, 2H), 1.09 (s, 9H) 399.2179; found, 399.2183 159 HRMS-ESI ¹H NMR (300 MHz, CDCl₃) δ 9.20 (s, 2H), 9.08 (s, 1H), (m/z) 8.75 (dd, J = 2.3, 0.9 Hz, 1H), 7.94 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.81 (dd, J = 8.4, 1.0 Hz, 1H), 7.52-7.42 (m, 2H), calcd for 7.22-7.14 (m, 2H), 6.39 (s, 1H), 2.03-1.87 (m, 1H), C₂₃H₂₆N₃O, 1.08 (s, 9H), 1.06-0.97 (m, 2H), 0.75 (dt, J = 6.8, 4.7 Hz, 360.2070; 2H) found, 360.2077 160 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.77 (dd, J = 2.4, 0.8 Hz, 1H), 7.95 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.91-7.73 (m, 1H), 7.64-7.48 (m, 4H), 6.26 (s, calcd for 1H), 1.44-1.37 (m, 2H), 1.13-1.03 (m, 11H) C₂₄H₂₅F₃N₃O, ¹⁹F NMR (376 MHz, CDCl₃) δ −70.00 428.1944; found, 428.1949 161 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.09 (s, 1H), (m/z) 8.81-8.73 (m, 1H), 7.95 (dd, J = 8.3, 2.4 Hz, 1H), 7.89- [M + H]⁺ 7.81 (m, 1H), 7.65-7.56 (m, 2H), 7.40-7.31 (m, 2H), calcd for 6.15 (s, 1H), 1.09 (s, 9H) C₂₂H₂₁F₅N₃O₂, ¹⁹F NMR (376 MHz, CDCl₃) δ −85.95, −87.71 454.1548; found, 454.1553 162 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.08 (s, 1H), (m/z) 8.70 (s, 1H), 7.93 (dt, J = 8.5, 1.8 Hz, 1H), 7.82 (dd, J = [M + H]⁺ 8.4, 0.9 Hz, 1H), 7.36 (t, J = 8.7 Hz, 1H), 6.82 (dd, J = calcd for 8.6, 2.6 Hz, 1H), 6.76 (dd, J = 12.5, 2.5 Hz, 1H), 6.34 (s, C₂₁H₂₃FN₃O₂, 1H), 3.86 (s, 3H), 1.08 (s, 9H) 368.1769; ¹⁹F NMR (376 MHz, CDCl₃) δ −115.26 found, 368.1773 163 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.62 (dd, J = 2.3, 1.0 Hz, 1H), 7.86 (dd, J = 8.4, 2.2 Hz, [M + H]⁺ 1H), 7.82 (dd, J = 8.3, 1.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, calcd for 1H), 7.00-6.90 (m, 2H), 6.28 (s, 1H), 3.88 (s, 3H), 1.07 C₂₂H₂₃F₃N₃O₃, (s, 9H) 434.1686; ¹⁹F NMR (376 MHz, CDCl₃) δ −57.13 found, 434.1695 164 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 2H), 9.09 (s, 1H), (m/z) 8.70 (s, 1H), 7.98-7.89 (m, 1H), 7.85 (dd, J = 8.4, 1.0 [M + H]⁺ Hz, 1H), 7.43 (td, J = 8.6, 6.3 Hz, 1H), 7.08-6.91 (m, calcd for 2H), 6.17 (s, 1H), 1.09 (s, 9H) C₂₀H₂₀F₂N₃O, ¹⁹F NMR (376 MHz, CDCl₃) δ −108.87 (d, J = 8.1 356.1569; Hz), −113.11 (d, J = 8.1 Hz) found, 356.1572 165 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 2H), 9.08 (s, 1H), (m/z) 8.75 (dd, J = 2.4, 0.9 Hz, 1H), 7.93 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.87-7.78 (m, 3H), 7.35-7.28 (m, 2H), 6.17 (s, calcd for 1H), 1.08 (s, 9H) C₂₀H₂₁IN₃O, 446.0724; found, 446.0727 166 HRMS-ESI ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), (m/z) 8.60 (t, J = 1.6 Hz, 1H), 7.85 (t, J = 1.7 Hz, 2H), 7.37- [M + H]⁺ 7.25 (m, 2H), 7.11 (td, J = 8.2, 2.6 Hz, 1H), 6.18 (s, 1H), calcd for 1.09 (s, 9H) C₂₀H₂₀ClFN₃O, ¹⁹F NMR (376 MHz, CDCl₃) δ −111.02 372.1273; found, 372.1275 167 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.74 (dd, J = m/z 434 2.4, 0.8 Hz, 1H), 8.67 (s, 1H), 7.82 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.77 (dd, J = 8.4, 0.8 Hz, 1H), 7.64-7.59 (m, 2H), 7.33 (d, J = 7.9 Hz, 2H), 5.71 (s, 1H), 3.82 (s, 3H), 1.17 (s, 9H) ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 (s) 168 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.75 (dd, J = m/z 406 2.3, 0.6 Hz, 1H), 8.66 (s, 1H), 7.84 (dd, J = 8.4, 2.4 Hz, [M + H]⁺ 1H), 7.70 (dd, J = 8.4, 0.7 Hz, 1H), 7.56-7.53 (m, 2H), 7.53-7.49 (m, 2H), 5.78 (s, 1H), 3.78 (s, 3H), 1.37 (s, 9H), 1.17 (s, 9H) ¹³C NMR (101 MHz, CDCl₃) δ 166.48, 160.91, 157.47, 156.62, 151.29, 144.93, 134.55, 134.42, 133.66, 126.65, 126.07, 124.38, 122.89, 80.20, 53.39, 40.20, 34.64, 31.31, 26.82 169 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.74 (d, J = m/z 415 2.2 Hz, 1H), 8.66 (s, 1H), 7.83 (dd, J = 8.4, 2.4 Hz, 1H), [M + H]⁺ 7.76 (dd, J = 8.4, 0.7 Hz, 1H), 7.61-7.57 (m, 2H), 7.43- 7.38 (m, 2H), 5.73 (s, 1H), 3.82 (s, 3H), 1.79 (q, J = 5.1 Hz, 2H), 1.46 (q, J = 5.2 Hz, 2H), 1.17 (s, 9H) ¹³C NMR (101 MHz, CDCl₃) δ 166.40, 161.79, 157.61, 156.62, 144.95, 136.84, 136.09, 133.77, 127.49, 126.43, 124.12, 123.04, 122.28, 80.36, 53.46, 40.35, 26.78, 18.40, 13.66 170 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.78 (dd, J = m/z 375 2.3, 0.8 Hz, 1H), 8.67 (s, 1H), 7.87 (dd, J = 8.4, 2.3 Hz, [M + H]⁺ 1H), 7.83 (dd, J = 8.4, 0.9 Hz, 1H), 7.81-7.77 (m, 2H), 7.73-7.69 (m, 2H), 5.66 (s, 1H), 3.85 (s, 3H), 1.16 (s, 9H) ¹³C NMR (101 MHz, CDCl₃) δ 166.33, 163.18, 157.72, 156.67, 145.15, 141.96, 134.07, 132.89, 132.82, 127.64, 123.73, 123.22, 118.56, 111.90, 80.52, 53.60, 40.51, 26.72 171 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.76 (dd, J = m/z 381 2.3, 0.8 Hz, 1H), 8.67 (s, 1H), 8.47 (d, J = 1.8 Hz, 1H), [M + H]⁺ 8.36 (d, J = 2.8 Hz, 1H), 7.86 (dd, J = 8.4, 2.3 Hz, 1H), 7.81 (dd, J = 8.4, 0.9 Hz, 1H), 7.38 (dd, J = 2.7, 1.9 Hz, 1H), 5.70 (s, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 1.17 (s, 9H) ¹³C NMR (101 MHz, CDCl₃) δ 166.36, 162.61, 157.64, 156.65, 155.85, 145.12, 140.42, 136.99, 134.09, 133.73, 131.48, 123.90, 123.18, 118.87, 80.42, 55.71, 53.56, 40.42, 26.75 172 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 8.97 (d, J = m/z 419 1.5 Hz, 1H), 8.80 (d, J = 1.5 Hz, 1H), 8.68 (s, 1H), 8.08 [M + H]⁺ (dd, J = 8.1, 2.1 Hz, 1H), 7.90 (d, J = 1.6 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 5.63 (s, 1H), 3.87 (s, 3H), 1.17 (s, 9H) ¹⁹F NMR (376 MHz, CDCl₃) δ −67.83 (s) 173 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.70 (s, 2H), 9.21 (d, J = m/z 419.5 1.8 Hz, 1H), 9.14 (s, 1H), 8.67 (d, J = 2.8 Hz, 1H), 8.37 [M + H]⁺ (dd, J = 8.4, 2.4 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 3.18 (d, J = 15.4 Hz, 3H), 0.87 (d, J = 13.6 Hz, 9H). ¹⁹F NMR (376 MHz, CDCl₃) δ −58.12 (s). 174 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.47 (s, 1H), 9.10 (d, J = m/z 405.46 1.6 Hz, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.52-8.47 (m, 2H), [M + H]⁺ 8.38 (d, J = 8.4 Hz, 1H), 8.29 (dd, J = 8.8, 2.4 Hz, 1H), 7.80-7.87 (m, 1H), 7.67-7.64 (m, 1H), 6.76 (s, 1H), 1.01 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 160.73, 157.84, 153.18, 145.86, 145.43, 144.72, 143.07, 142.53, 141.084, 134.17, 132.26, 129.21, 124.04, 121.69, 120.98, 80.25, 41.08, 26.01. 175 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 2H), 9.10 (s, 1H), m/z 412.5 8.75 (d, J = 1.6 Hz, 1H), 8.02 (dd, J = 8.3, 2.3 Hz, 1H), [M + H]⁺ 7.95-7.91 (m, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.3, 2.1 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 5.81 (s, 1H), 1.80 (s, 6H), 1.10 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 161.16, 157.01, 156.41, 146.60, 142.76, 140.39, 136.75, 136.73, 132.24, 130.71, 130.63, 130.44, 123.12, 122.12, 122.08, 117.50, 112.30, 40.25, 36.95, 28.90, 26.30. 176 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.84 (s, 2H), m/z 436.45 8.74 (s, 1H), 7.90 (td, J = 1.9, 8.3 Hz, 1H), 7.59 (d, J = 8.4 [M + H]⁺ Hz, 1H), 7.55-7.45 (m, 1H), 7.14 (br t, J = 10.3 Hz, 2H), 3.26-2.97 (m, 3H), 1.18 (t, J = 7.0 Hz, 3H), 0.88 (t, J = 7.3 Hz, 6H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.96 −113.18. 177 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 1H), 8.83 (s, 2H), m/z 390.44 8.73 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 2.2, 8.1 Hz, 1H), 7.72 [M + H]⁺ (d, J = 7.8 Hz, 1H), 7.60-7.53 (m, 2H), 7.32 (d, J = 8.3 Hz, 2H), 3.47 (dquin, J = 1.7, 6.8 Hz, 2H), 2.05 (s, 3H), 1.33 (t, J = 6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃): δ 162.44, 157.24, 155.16, 149.27, 147.16, 138.99, 136.15, 135.24, 121.99, 121.54, 120.43, 119.17, 79.62, 58.71, 24.03, 15.62. 178 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.85 (s, 1H), 8.58 (s, 1H), m/z 399 8.43 (s, 2H), 7.82 (dd, J = 8.0, 2.0 Hz, 1H), 7.53-7.47 [M + H]⁺ (m, 3H), 7.37 (d, J = 8.0 Hz, 2H), 5.29 (bs, 1H), 3.33 (d, J = 14.4 Hz, 1H) 3.27 (d, J = 14.0 Hz, 1H), 1.78 (dd, J = 7.6, 3.2 Hz, 2H), 1.47 (dd, J = 7.2, 4.8 Hz, 2H), 1.05 (s, 9H). 179 HRMS-ESI ¹H NMR (300 MHz, DMSO-d6) d 9.46 (s, 2H), 9.06 (s, (m/z) 1H), 8.62 (dd, J = 2.3, 0.8 Hz, 1H), 7.91 (dd, J = 8.3, 0.9 [M + H]⁺ Hz, 1H), 7.84 (dd, J = 8.3, 2.3 Hz, 1H), 7.51 (d, J = 2.1 calcd for Hz, 1H), 7.44 (dd, J = 8.0, 2.1 Hz, 1H), 7.30 (d, J = 8.0 C₂₆H₃₀N₄O, Hz, 1H), 6.26 (s, 1H), 2.58 (q, J = 7.5 Hz, 2H), 1.73 (s, 414.2420; 6H), 1.03 (t, J = 7.5 Hz, 3H), 0.94 (s, 9H). found, ¹³C NMR (126 MHz, DMSO) d 162.42, 157.08, 156.90, 414.2425 147.06, 142.58, 141.92, 137.10, 134.83, 131.03, 126.05, 125.09, 123.32, 122.48, 79.36, 37.06, 28.79, 26.26, 26.24, 15.79. 180 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.80 (bs, 1H), 8.71 (d, J = m/z 419 2.0 Hz, 1H), 8.58 (bs, 2H), 8.37-8.35 (m, 2H), 7.84 (dt, [M + H]⁺ J = 8.8, 2.4 Hz, 2H), 6.96 (d, J = 8.8 Hz, 1H), 6.73 (s, 1H), 4.82 (q, J = 8.4 Hz, 2H), 1.01 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 161.64, 159.27, 145.79, 144.70, 144.17, 142.48, 137.97, 133.90, 131.70, 128.08, 124.98, 124.18, 122.22, 111.44, 80.20, 62.44, 41.02, 26.02. 181 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 8.84 (s, 1H), 8.59 (d, J = m/z 390.42 2.1 Hz, 1H), 8.45 (s, 1H), 8.44 (s, 2H), 7.85 (d, J = 8.4, [M + H]⁺ 2.1 Hz, 1H), 7.49-7.46 (m, 4H), 5.72 (bs, 1H), 3.30 (d, J = 13.8 Hz, 1H); 3.26 (d, J = 13.8 Hz, 1H), 1.35 (s, 9H), 1.02 (s, 9H). 182 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.99 (s, 2H), m/z 418.4 8.69 (s, 1H), 7.91 (s, 2H), 7.44 (t, J = 8.6 Hz, 1H), 7.18- [M + H]⁺ 7.07 (m, 2H), 3.45 (s, 3H), 2.08 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 161.01, 159.65, 158.51, 157.97, 155.95, 149.77, 149.13, 149.10, 137.21, 137.18, 135.64, 131.16, 131.12, 129.71, 123.88, 123.75, 121.58, 120.41, 119.04, 117.04, 109.79, 109.52, 88.24, 79.10, 75.84, 52.70. NMR (376 MHz, CDCl₃): δ −57.99, −113.26. 183 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.15 (d, J = m/z 388.5 1.5 Hz, 1H), 9.09 (s, 1H), 8.86 (d, J = 1.9 Hz, 1H), 8.42 [M + H]⁺ (dd, J = 8.5, 2.3 Hz, 1H), 7.97-7.86 (m, 2H), 7.79 (dd, J = 8.3, 0.7 Hz, 1H), 6.18 (s, 1H), 1.82 (s, 6H), 1.08 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 160.82, 156.93, 156.41, 153.53, 147.15, 145.52, 137.00, 136.57, 135.09, 134.27, 133.32, 123.23, 122.24, 120.32, 40.18, 35.54, 28.88, 26.31. 184 ESIMS ¹H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.95 (s, m/z 406.38 2H), 8.68 (s, 1H), 8.09-8.02 (m, 1H), 7.90 (d, J = 8.4 Hz, [M + H]⁺ 1H), 7.77 (t, J = 8.6 Hz, 1H), 7.57 (d, J = 11.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 5.99 (s, 1H), 2.06-1.93 (m, 1H), 0.66-0.49 (m, 3H), 0.48-0.34 (m, 1H). ¹⁹F NMR (282.2 MHz, DMSO-d6) δ −56.96-113.68. 185 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 9.01 (s, 2H), m/z 404.31 8.70 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, [M + H]⁺ 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.20-7.08 (m, 2H), 6.24 (s, 1H), 2.01 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 160.99, 159.21, 158.48, 158.02, 149.89, 147.30, 147.27, 138.16, 138.12, 137.76, 131.18, 131.14, 130.40, 123.46, 123.32, 121.58, 121.00, 119.01, 117.17, 109.85, 109.59, 85.30, 79.16, 70.75, 3.83. ¹⁹F NMR (376 MHz, CDCl₃): δ −57.98, −113.28. 186 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H) 9.04 (d, J = m/z 449 2.0 Hz, 1H), 8.66 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H) 8.23 [M + H]⁺ (dd, J = 8.0, 2.4 Hz, 1H)7.74 (dd, J = 8.8, 5.2 Hz, 2H), 7.40-7.35 (m, 1H) 5.76 (s, 1H), 4.47 (q, J = 8.0 Hz, 2H) 3.82 (s, 3H), 1.16 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 166.47, 162.47, 157.33, 156.61, 153.20, 149.00, 144.76, 138.19, 133.48, 132.36, 124.32, 124.18, 121.91, 122.79, 121.55, 120.90, 80.26, 66.13, 53.46, 40.18, 26.75. ¹⁹F NMR (282 MHz, CDCl₃) δ −73.80 (t). 187 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.67 (d, J = m/z 451 4.0 Hz, 2H), 7.85-7.76 (m, 2H), 7.49 (t, J = 17.2 Hz, [M + H]⁺ 1H), 7.13 (q, J = 9.2 Hz, 2H), 5.69 (bs, 1H) 3.82 (s, 3H), 1.17 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 166.42, 162.27, 161.00, 158.50, 157.48, 156.60, 149.57, 149.46, 146.39, 146.36, 135.75, 135.71, 131.12, 131.10, 128.59, 124.16, 124.02, 122.79, 121.59, 119.02, 117.07, 117.04, 109.81, 109.54, 80.37, 53.51, 40.33, 26.73. ¹⁹F NMR (282 MHz, CDCl₃) δ −57.9, −113.2 (t). 188 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.47 (s, 1H), 8.75 (d, J = m/z 3 87.51 2.4 Hz, 1H), 8.53-8.46 (m, 2H), 8.35 (d, J = 8.4 Hz, [M + H]⁺ 1H), 7.87 (dd, J = 8.1, 2.1 Hz, 1H), 7.62-7.56 (m, 4H), 6.78 (s, 1H), 1.77 (s, 6H), 1.01 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 158.94, 158.11, 145.76, 144.48, 144.46, 141.36, 141.09, 137.02, 134.32, 134.17, 127.56, 125.881, 124.26, 124.04, 80.09, 40.99, 36.97, 29.08, 26.03. 189 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.74 (s, 2H), 9.15 (s, 1H), m/z 460.47 8.82 (s, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.3 Hz, [M + H]⁺ 1H), 7.52 (t, J = 8.6 Hz, 1H), 7.20-7.07 (m, 2H), 3.89 (t, J = 2.4 Hz, 2H), 2.55 (t, J = 2.4 Hz, 1H), 0.93 (s, 9H). ¹⁹F NMR (376 MHz, CDCl₃) δ −57.96-113.17. 190 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 1H), 8.82 (s, 2H), m/z 422.46 8.67 (s, 1H), 7.84 (td, J = 1.8, 8.2 Hz, 1H), 7.73 (d, J = 8.3 [M + H]⁺ Hz, 1H), 7.45 (t, J = 8.3 Hz, 1H), 7.12 (br dd, J = 10.0, 14.9 Hz, 2H), 3.36 (dq, J = 2.0, 7.0 Hz, 2H), 2.69 (qd, J = 7.3, 14.7 Hz, 1H), 2.50 (qd, J = 7.3, 14.7 Hz, 1H), 1.33 (t, J = 6.8 Hz, 3H), 0.77 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.18, 160.99, 158.48, 157.17, 155.52, 149.60, 148.54, 148.51, 137.66, 136.82, 136.79, 131.15, 131.10, 128.85, 124.15, 121.59, 121.00, 119.02, 117.06, 109.79, 109.52, 81.92, 57.87, 26.92, 6.89. ¹⁹F NMR (376 MHz, CDCl₃): δ −57.98, −113.30. 191 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.17 (s, 1H), 8.89 (s, 2H), m/z 428.4 8.81 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 2.4, 8.3 Hz, 1H), [M + H]⁺ 7.67-7.59 (m, 3H), 7.35 (d, J = 8.1 Hz, 2H), 3.84 (dd, J = 2.6, 4.8 Hz, 2H), 3.07 (hept, J = 6.8 Hz, 1H), 2.35 (t, J = 2.4 Hz, 1H), 0.89 (dd, J = 6.6, 17.2 Hz, 6H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.8. 192 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.69 (s, 2H), 9.13 (s, 1H), m/z 399.6 8.87 (d, J = 1.8 Hz, 1H), 7.91 (dd, J = 8.4, 2.4 Hz, 1H), [M + H]⁺ 7.66 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 3.19 (s, 3H), 1.80 (q, J = 5.0 Hz, 2H), 1.48 (q, J = 5.3 Hz, 2H), 0.90 (s, 9H). IR (ATR) 2961, 2234, 1411, 1071 cm⁻¹. 193 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.13 (s, 1H), 8.84 (s, 2H), m/z 402.42 8.73 (d, J = 1.8 Hz, 1H), 7.92-7.83 (m, 1H), 7.75 (d, J = [M + H]⁺ 8.4 Hz, 1H), 7.63-7.51 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 3.33 (s, 3H), 1.76-1.66 (m, 1H), 0.73 (m, 2H), 0.55- 0.43 (m, 1H), 0.40-0.29 (m, 1H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.8. 194 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.15 (s, 1H), 8.85 (s, 2H), m/z 404.40 8.81 (d, J = 2.2 Hz, 1H), 7.91 (dd, J = 2.4, 8.3 Hz, 1H), [M + H]⁺ 7.63 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 3.05 (s, 4H), 0.88 (t, J = 7.2 Hz, 6H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.8. 195 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 8.86 (s, 1H), 8.56 (d, J = m/z 433 1.8 Hz, 1H), 8.44 (s, 2H), 8.31(d, J = 1.8 Hz, 1H), 7.84- [M + H]⁺ 7.77 (m, 2H), 7.51(d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.53 (bs, 1H), 4.83 (d, J = 8.7 Hz, 1H), 4.78 (d, J = 8.4 Hz, 1H), 3.34 (d, J = 13.8 Hz, 1H), 3.28 (d, J = 13.8 Hz, 1H), 1.02 (s, 9H). 196 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 8.67 (s, 1H), m/z 431.6 8.48 (d, J = 1.9 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.60 [M + H]⁺ (dd, J = 8.3, 2.3 Hz, 1H), 7.41 (s, 1H), 7.37 (dd, J = 8.1, 1.9 Hz, 1H), 7.24 (s, 1H), 5.74 (s, 1H), 3.81 (s, 3H), 2.30 (s, 3H), 1.77 (s, 6H), 1.18 (s, 9H). IR (ATR) 2957, 2236, 1470, 1005 cm⁻¹. 197 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.74 (s, 2H), 9.15 (s, 1H), m/z 442.42 8.87 (d, J = 2.2 Hz, 1H), 7.94 (dd, J = 2.6, 8.4 Hz, 1H), [M + H]⁺ 7.81 (d, J = 8.4 Hz, 1H), 7.70-7.58 (m, 2H), 7.36 (d, J = 8.1 Hz, 2H), 3.89 (d, J = 1.1 Hz, 2H), 2.55 (, J = 2.4 Hz, 1H), 0.93 (s, 9H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.8. 198 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.65 (s, 2H), 9.12 (s, 1H), m/z 432.46 8.86 (d, J = 2.2 Hz, 1H), 7.89 (dd, J = 2.2, 8.4 Hz, 1H), [M + H]⁺ 7.68-7.59 (m, 3H), 7.35 (d, J = 8.1 Hz, 2H), 3.32-3.14 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H), 0.91 (s, 9H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.8. 199 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H) 9.09 (d, J = m/z 434 2.0 Hz, 1H), 8.67-8.63 (m, 2H) 8.27 (dd, J = 8.8, 2.0 [M + H]⁺ Hz, 1H), 7.83-7.65 (m, 3H), 5.71 (s, 1H), 3.79 (s, 3H), 1.16 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 166.46, 163.45, 157.41, 156.67, 153.12, 145.44, 145.15, 143.08, 133.91, 131.80, 129.24, 124.01, 123.00, 121.70, 120.95, 119.12, 80.38, 53.51, 40.26, 26.75. ¹⁹F NMR (282 MHz, CDCl₃) δ −58.13 200 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.85 (s, 2H), m/z 420.13 8.68 (s, 1H), 7.89 (td, J = 2.0, 8.3 Hz, 1H), 7.76 (d, J = 8.8 [M + H]⁺ Hz, 1H), 7.47 (t, J = 8.3 Hz, 1H), 7.19-7.03 (m, 2H), 3.34 (s, 3H), 1.72 (tt, J = 5.4, 8.5 Hz, 1H), 0.78-0.67 (m, 2H), 0.50 (td, J = 4.6, 9.3 Hz, 1H), 0.41-0.28 (m, 1H). ¹⁹F NMR (376 MHz, CDCl₃) δ −57.95 −113.26. 201 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J = 1.2 Hz, 1H), m/z 389 8.23 (d, J = 7.5 Hz, 2H), 7.81 (dd, J = 8.1, 2.1 Hz, 1H), [M + H]⁺ 7.55-7.47 (m, 6H), 7.00-6.90 (m, 1H), 3.33 (s, 2H), 1.35 (s, 9H), 1.04 (s, 9H). 202 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.85 (s, 1H), 8.76-8.72 m/z 421.5 (m, 1H), 8.33 (d, J = 2.8 Hz, 1H), 8.01-7.95 (m, 1H), [M + H]⁺ 7.93 (dd, J = 8.4, 2.3 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.63-7.57 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.28 (s, 1H), 1.09 (s, 9H). ¹⁹F NMR (376 MHz, CDCl₃) δ −57.81 (s), −127.51 (s). 203 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.71 (d, J = m/z 448 2.0 Hz, 1H), 8.67 (s, 1H), 7.80 (dd, J = 8.4, 2.8 Hz, 1H), [M + H]⁺ 7.72 (d, J = 8.0, Hz, 1H) 7.56 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 5.70 (bs, 1H) 4.41 (q, J = 8.0 Hz, 2H), 3.82 (s, 3H), 1.17 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 166.50, 166.99, 157.45, 157.29, 156.49, 144.74, 133.91, 133.52, 131.73, 128.35, 124.62, 124.29, 122.94, 121.86, 115.55, 80.23, 65.87, 53.49, 40.25, 26.75. ¹⁹F NMR (276 MHz, CDCl₃) δ −73.88 (t). 204 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.99 (s, 2H), m/z 432.42 8.68 (s, 1H), 7.96-7.85 (m, 2H), 7.44 (t, J = 8.3 Hz, 1H), [M + H]⁺ 7.17-7.06 (m, 2H), 3.78-3.68 (m, 1H), 3.62-3.51 (m, 1H), 2.06 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.06, 160.14, 158.51, 157.87, 155.90, 149.72, 149.63, 149.04, 149.01, 137.19, 137.16, 131.15, 131.10, 129.60, 123.95, 123.81, 121.59, 120.23, 119.04, 117.06, 109.78, 109.52, 87.67, 78.36, 60.85, 15.25. ¹⁹F NMR (376 MHz, CDCl₃): δ −57.99, −113.27. 205 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.95 (s, 2H), m/z 394.4 8.70 (s, 1H), 7.90 (td, J = 2.0, 8.3 Hz, 1H), 7.50-7.42 (m, [M + H]⁺ 2H), 7.19-7.09 (m, 2H), 5.77 (s, 1H), 2.42-2.31 (m, 2H), 0.93 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 160.94, 158.45, 157.36, 155.04, 149.80, 147.47, 139.13, 137.75, 131.12, 129.64, 123.50, 121.57, 119.72, 109.84, 109.58, 75.59, 33.78, 7.64. 206 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.10 (s, 1H), 8.83 (s, 2H), m/z 394.2 8.68 (s, 1H), 7.86 (td, J = 1.9, 8.3 Hz, 1H), 7.71 (d, J = 8.4 [M + H]⁺ Hz, 1H), 7.49-7.38 (m, 1H), 7.17-7.07 (m, 2H), 3.34 (s, 3H), 2.04 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 162.39, 161.03, 158.51, 157.33, 149.67, 149.58, 148.57, 148.54, 138.48, 137.08, 137.05, 131.16, 129.13, 124.10, 123.96, 121.60, 120.24,, 119.03, 117.04, 117.06, 109.79, 109.52, 80.05, 51.06, 23.31. 207 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.47 (s, 1H), 8.37 (s, 1H), m/z 404.2 8.52 (s, 1H), 8.48-8.47 (m, 1H), 8.35 (d, J = 8.4 Hz, 1H), [M + H]⁺ 7.85 (dd, J = 8.7, 2.4 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H), 6.75 (s, 1H), 0.95 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 159.18, 158.04, 149.27, 145.82, 144.52, 142.49, 141.09, 136.17, 134.21, 133.94 128.49, 124.05, 122.53, 80.13, 41.02, 26.05. 208 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.17 (s, 1H), 8.90 (s, 2H), m/z 446.45 8.75 (s, 1H), 7.97-7.86 (m, 1H), 7.66 (d, J = 8.4 Hz, 1H), [M + H]⁺ 7.51 (t, J = 8.6 Hz, 1H), 7.15 (t, J = 10.8 Hz, 2H), 3.86 (dd, J = 2.6, 4.0 Hz, 2H), 3.07 (td, J = 6.8, 13.6 Hz, 1H), 2.35 (t, J = 2.4 Hz, 1H), 0.90 (dd, J = 6.8, 15.6 Hz, 6H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.96 −113.15. 210 ESIMS ¹H NMR (500 MHz, CDCl₃) δ 9.23 (s, 2H), 9.09 (s, 1H), m/z 440.5 8.67 (s, 1H), 7.89 (s, 2H), 6.97 (d, J = 7.8 Hz, 2H), 6.01 [M + H]⁺ (s, 1H), 1.09 (s, 9H). IR (ATR) 2958, 1410, 1213, 1035 cm⁻¹. 211 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.69 (s, 2H), 9.13 (s, 1H), m/z 436.4 8.82 (s, 1H), 7.91 (td, J = 2.0, 8.3 Hz, 1H), 7.69 (d, J = 7.8 [M + H]⁺ Hz, 1H), 7.52 (t, J = 8.3 Hz, 1H), 7.20-7.08 (m, 2H), 3.20 (s, 1H), 0.90 (s, 9H). ¹⁹F NMR (376 MHz, CDCl₃): δ −57.97, −113.22 (t). 212 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.23 (s, 2H), 9.09 (s, 1H), m/z 413.4 8.53 (d, J = 1.4 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.74 [M + H]⁺ (dd, J = 8.2, 2.1 Hz, 1H), 7.34 (d, J = 7.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 1H), 6.31 (s, 1H), 2.93-2.78 (m, 2H), 2.75- 2.58 (m, 2H), 2.56-2.39 (m, 1H), 2.30 (s, 3H), 2.20- 2.03 (m, 1H), 1.09 (s, 9H). IR (ATR) 2955, 2230, 1409, 909 cm⁻¹. 213 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 1H), 8.81 (s, 2H), m/z 390.38 8.75-8.68 (m, 1H), 7.84 (dd, J = 2.4, 8.3 Hz, 1H), 7.68 (d, [M + H]⁺ J = 8.3 Hz, 1H), 7.59-7.53 (m, 2H), 7.32 (d, J = 8.3 Hz, 2H), 3.32 (s, 3H), 2.69 (qd, J = 7.3, 14.7 Hz, 1H), 2.50 (qd, J = 7.3, 14.7 Hz, 1H), 0.78 (t, J = 7.3 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃): δ 161.41, 157.22, 155.60, 149.30, 147.30, 137.38, 136.15, 134.99, 133.86, 128.51, 121.52, 121.38, 82.34, 50.43, 26.40; 7.64. 214 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.69 (s, 2H), 9.13 (s, 1H), m/z 401.6 8.89 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 8.4, 2.5 Hz, 1H), [M + H]⁺ 7.65 (dt, J = 18.9, 7.2 Hz, 5H), 3.20 (s, 3H), 1.79 (s, 6H), 0.90 (s, 9H). IR (ATR) 2978, 2236, 1411, 1069 cm⁻¹. 215 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.09 (s, 1H), 8.84 (s, 2H), m/z 408.2 8.67 (s, 1H), 7.90-7.79 (m, 1H), 7.77-7.66 (m, 1H), [M + H]⁺ 7.48-7.40 (m, 1H), 7.18-7.06 (m, 2H), 3.48 (q, J = 7.0 Hz, 2H), 2.05 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 162.39, 161.03, 158.51, 157.33, 149.67, 149.58, 148.57, 148.54, 138.48, 137.08, 137.05, 131.16, 129.13, 124.10, 123.96, 121.60, 120.24,, 119.03, 117.04, 117.06, 109.79, 109.52, 80.05, 51.06, 23.31. 216 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.23 (s, 2H), 9.09 (s, 1H), m/z 433.5 8.59 (dd, J = 2.0, 1.0 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), [M + H]⁺ 7.84 (d, J = 1.0 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.0, 2.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.30 (s, 1H), 2.42 (s, 3H), 1.79 (s, 6H), 1.09 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 159.25, 158.68, 156.90, 156.43, 147.21, 142.40, 138.62, 137.54, 137.11, 135.79, 134.67, 130.58, 124.07, 122.80, 121.73, 121.49, 40.14, 37.26, 29.11, 26.35, 15.97. 217 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.99 (s, 2H), m/z 400.44 8.75 (t, J = 1.5 Hz, 1H), 7.93-7.84 (m, 2H), 7.62-7.48 (m, [M + H]⁺ 2H), 7.32 (d, J = 7.7 Hz, 2H), 3.44 (s, 3H), 2.08 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 159.26, 157.95, 149.38, 147.89, 135.89, 135.72, 135.33, 134.65, 128.58, 121.54, 120.64, 88.19, 79.05, 75.85, 52.68, 3.93. 218 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.19 (s, 1H), 8.71 (s, 1H), m/z 449 8.66 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, [M + H]⁺ 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H) 5.70 (s, 1H), 4.82 (q, J = 8.4 Hz, 2H), 3.82 (s, 3H), 1.17 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 166.3, 162.0, 161.5, 157.5, 156.5, 144.6, 137.87, 133.50, 131.16, 128.02, 125.42, 123.93, 123.15, 121.74, 111.36, 80.34, 62.20, 53.44, 40.34, 26.68 20.4. ¹⁹F NMR (276 MHz, CDCl₃) δ −73.7 (t). 219 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.85 (s, 1H), 8.62 (d, J = m/z 434 1.6 Hz, 1H), 8.45 (s, 2H), 7.87 (dd, J = 10.8, 6.0 Hz, 1H), [M + H]⁺ 7.74 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 3.34 (t, J = 21.6 Hz, 2H), 1.02 (s, 9H). 220 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 2H), 9.12 (s, 1H), m/z 450.47 8.80 (s, 1H), 7.89 (td, J = 1.8, 8.6 Hz, 1H), 7.66 (d, J = 8.3 [M + H]⁺ Hz, 1H), 7.52 (t, J = 8.6 Hz, 1H), 7.19-7.07 (m, 2H), 3.35-3.16 (m, 2H), 1.33 (t, J = 6.8 Hz, 3H), 0.91 (s, 9H). ¹⁹F NMR (376 MHz, CDCl₃) δ −57.96 −113.22. 221 ESIMS ¹H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.94 (s, m/z 380.38 2H), 8.69 (s, 1H), 8.03 (td, J = 1.7, 8.3 Hz, 1H), 7.90 (d, [M + H]⁺ J = 8.4 Hz, 1H), 7.75 (t, J = 8.8 Hz, 1H), 7.56 (d, J = 11.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.47 (s, 1H), 1.96 (s, 3H). 222 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.20 (s, 1H), 8.67 (s, 1H), m/z 448 8.46 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.58 [M + H]⁺ (dd, J = 8.1, 2.1 Hz, 1H), 7.24 (d, J = 9.6 Hz, 1H), 7.13 (d, J = 11.4 Hz, 2H) 5.72 (bs, 1H). 82 (s, 3H), 2.27 (s, 3H) 1.17 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 166.47,, 161.48, 157.45, 156.57, 148.90, 146.67, 137.85, 136.44, 136.06, 134.36, 131.12, 124.22, 122.71, 122.45, 122.19, 118.77, 118.40, 80.32, 53.42, 40.27, 26.76, 20.49. ¹⁹F NMR (282 MHz, CDCl₃) δ −57.9. 223 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 2H), 9.09 (s, 1H), m/z 401.6 8.53 (d, J = 1.5 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.74 [M + H]⁺ (dd, J = 8.3, 2.1 Hz, 1H), 7.45-7.34 (m, 2H), 7.24 (d, J = 8.0 Hz, 3H), 6.30 (s, 1H), 2.30 (s, 3H), 1.77 (s, 6H), 1.09 (s, 9H). IR (ATR) 2979, 2238, 1409, 1071 cm⁻¹. 224 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.47 (s, 1H), 8.53-8.47 m/z 418.43 (m, 3H), 8.33 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 8.4, 2.1 [M + H]⁺ Hz, 1H), 7.26-7.21 (m, 1H), 7.15-7.10 (m, 2H), 6.78 (s, 1H), 2.26 (s, 3H), 1.01 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 158.63, 158.14, 148.88, 146.13, 145.80, 142.49, 141.13, 137.91, 136.42, 136.32, 134.82, 131.16, 123.52, 122.71, 118.38, 80.11, 41.022, 26.055, 20.54. 225 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.45 (s, 1H), 8.72 (d, J = m/z 418.43 2.0 Hz, 1H), 8.51 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.31 [M + H]⁺ (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 8.4, 2.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 4.43-4.37 (m, 2H), 1.01 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 158.31, 158.26, 157.45, 145.75, 144.25, 142.43, 141.10, 134.41, 133.90, 131.79, 128.42, 123.97, 115.54, 80.07, 66.12, 40.98, 26.04. 226 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), m/z 405.6 8.77-8.71 (m, 1H), 7.97 (ddd, J = 8.4, 2.2, 1.6 Hz, 1H), [M + H]⁺ 7.87 (dd, J = 8.4, 0.8 Hz, 1H), 7.54-7.37 (m, 2H), 7.32 (dd, J = 11.7, 1.9 Hz, 1H), 6.15 (s, 1H), 1.78 (s, 6H), 1.09 (s, 9H). IR (ATR) 2982, 2361, 1419, 1071 cm⁻¹. 227 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J = 1.8 Hz, 1H), m/z 398 8.23 (dd, J = 4.8, 1.8 Hz, 2H), 7.81 (dd, J = 8.1, 2.4 Hz, [M + H]⁺ 1H), 7.54-7.48 (m, 4H), 7.37 (d, J = 8.4 Hz, 2H), 6.99 (dd, J = 7.5, 4.8 Hz, 1H), 3.34 (s, 2H), 1.78 (dd, J = 7.5, 5.1 Hz, 2H), 1.44 (dd, J = 7.8, 4.8 Hz, 2H), 1.04 (s, 9H). 228 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.69 (s, 2H), 9.13 (s, 1H), m/z 419.5 8.83 (s, 1H), 7.98-7.88 (m, 1H), 7.68 (dd, J = 8.4, 0.8 [M + H]⁺ Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.1, 2.0 Hz, 1H), 7.33 (dd, J = 11.7, 1.9 Hz, 1H), 3.20 (s, 3H), 1.78 (s, 6H), 0.90 (s, 9H). IR (ATR) 2924, 2238, 1418, 1069 cm⁻¹. 229 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.47 (s, 1H), 8.74 (d, J = m/z 385.46 2.4 Hz, 1H), 8.51-8.47 (m, 2H), 8.34 (d, J = 8.4 Hz, 1H), [M + H]⁺ 7.86 (dd, J = 8.4, 2.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 6.90 (bs, 1H), 1.80-1.76 (m, 2H), 1.47-1.43 (m, 2H), 1.01 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 158.96, 158.11, 145.76, 144.42, 142.45, 141.08, 136.82, 136.06, 134.28, 134.11, 127.51, 126.32, 124.04, 122.26, 80.10, 40.99, 26.03, 18.40, 13.62. 230 ESIMS ¹H NMR (300 MHz, DMSO-d6) δ 9.08 (s, 2H), 9.03 (s, m/z 408.40 1H), 8.75 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 [M + H]⁺ Hz, 1H), 7.76 (t, J = 8.8 Hz, 1H), 7.56 (d, J = 11.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.06 (s, 1H), 3.08 (td, J = 6.8, 13.6 Hz, 1H), 0.80 (d, J = 7.0 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H). ¹⁹F NMR (282.2 MHz, DMSO-d6) δ −56.96 −113.68. 231 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1H), 8.24 (d, J = m/z 433 6.0 Hz, 2H), 7.84 (dd, J = 6.3, 1.8 Hz, 1H), 7.73 (d, J = [M + H]⁺ 6.3 Hz, 2H), 7.60-7.49 (m, 4H), 6.99 (dd, J = 5.7, 3.6 Hz, 1H), 2.61 (s, 2H), 1.05 (s, 9H). ¹³C NMR (75 MHz, CDCl₃): δ 160.0, 151.3, 147.1, 145.1, 139.6, 138.4, 136.8, 134.0, 133.4, 133.2, 127.9, 124.3, 122.1, 80.2, 39.5, 37.1, 29.6, 25.9 232 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.12 (s, 1H), 8.85 (s, 2H), m/z 416.42 8.72 (d, J = 2.2 Hz, 1H), 7.92-7.85 (m, 1H), 7.81-7.74 [M + H]⁺ (m, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 3.55-3.40 (m, 2H), 1.70 (tt, J = 5.5, 8.3 Hz, 1H), 1.27 (t, J = 7.0 Hz, 3H), 0.75-0.62 (m, 2H), 0.56-0.45 (m, 1H), 0.41-0.31 (m, 1H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.8. 233 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.68 (s, 1H), m/z 433.6 8.67 (s, 1H), 7.85-7.80 (m, 1H), 7.77 (dd, J = 8.4, 0.8 [M + H]⁺ Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.1, 1.9 Hz, 1H), 7.11 (dd, J = 11.4, 1.9 Hz, 1H), 5.71 (s, 1H), 3.82 (s, 3H), 1.82 (q, J = 5.1 Hz, 2H), 1.47 (q, J = 5.5 Hz, 2H), 1.17 (s, 9H). IR (ATR) 2969, 2237, 1738, 1471 cm⁻¹. 234 ESIMS 8.53 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 11.2 m/z 432 Hz, 2H), 7.77 (td, J = 8.8, 2.8 Hz, 2H), 7.54-7.47 (m, [M + H]⁺ 2H), 7.10 (m, 2H ), 4.78 (q, J = 16.8 Hz, 1H), 3.34 (s, 2H), 3.28 (s, 2H), 1.07 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 161.6, 159.5, 151.3, 147.1, 144.6, 138.4, 137.8, 133.5, 133.4, 131.1, 127.7, 122.5, 122.2, 111.3, 80.2, , 62.0, 39.5, 37.1, 25.9. 235 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J = 1.5 Hz, 1H), m/z 437.5 8.52 (dd, J = 8.0, 1.8 Hz, 1H), 8.30 (dd, J = 4.6, 1.8 Hz, [M + H]⁺ 1H), 7.77 (dd, J = 8.3, 2.3 Hz, 1H), 7.66-7.59 (m, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.30-7.26 (m, 2H), 5.59 (s, 1H), 1.26 (s, 9H). ¹⁹F NMR (376 MHz, CDCl₃) δ −57.82 (s). 236 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 9.08 (s, 1H), m/z 403.6 8.72 (d, J = 1.0 Hz, 1H), 7.98-7.92 (m, 1H), 7.86 (dd, J = [M + H]⁺ 8.4, 0.8 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 8.1, 1.9 Hz, 1H), 7.12 (dd, J = 11.5, 1.9 Hz, 1H), 6.14 (s, 1H), 1.83 (q, J = 5.1 Hz, 2H), 1.48 (q, J = 5.5 Hz, 2H), 1.09 (s, 9H). IR (ATR) 2969, 2238, 1421, 1205 cm⁻¹. 237 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.85 (s, 2H), m/z 418.18 8.69 (s, 1H), 7.87 (td, J = 2.0, 8.3 Hz, 1H), 7.76 (d, J = 8.3 [M + H]⁺ Hz, 1H), 7.45 (t, J = 8.6 Hz, 1H), 7.18-7.06 (m, 2H), 4.17 (t, J = 2.7 Hz, 2H), 2.44 (t, J = 2.4 Hz, 1H), 2.11 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.64, 161.06, 158.51, 157.53, 155.18, 149.74, 149.63, 148.62, 148.59, 138.114, 137.24, 137.22, 131.16, 131.12, 129.44, 123.98, 123.84, 121.60, 119.02, 117.06, 109.80, 109.54, 81.04, 79.85, 74.46, 52.29, 24.07. 238 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.11 (s, 1H), 8.85 (s, 2H), m/z 432.46 8.68 (s, 1H), 7.91-7.82 (m, 1H), 7.79-7.72 (m, 1H), [M + H]⁺ 7.50-7.39 (m, 1H), 7.18-7.04 (m, 2H), 4.06 (d, J = 2.2 Hz, 2H), 2.76-2.62 (m, 1H), 2.61-2.48 (m, 1H), 2.45 (t, J = 2.4 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 161.39, 160.91, 158.06, 157.45, 155.54, 149.72, 149.58, 148.62, 137.04, 136.99, 136.72, 131.16, 131.10, 129.28, 123.99, 123.80, 122.01, 121.26, 118.58, 117.05, 109.84, 109.84, 109.49, 83.36, 79.43, 74.40, 51.69, 27.16, 7.08. ¹⁹F NMR (282 MHz, CDCl₃): δ −57.98, −113.30. 239 HRMS-ESI ¹H NMR (300 MHz, DMSO-d6) d 9.46 (s, 2H), 9.06 (s, (m/z) 1H), 8.86 (dd, J = 2.3, 0.8 Hz, 1H), 8.70 (dd, J = 2.4, 0.7 [M + H]⁺ Hz, 1H), 8.07 (dd, J = 8.4, 2.3 Hz, 1H), 7.99-7.90 (m, calcd for 2H), 6.29 (s, 1H), 2.41 (d, J = 0.7 Hz, 3H), 1.78 (s, 6H), C₂₄H₂₇N₅O, 0.95 (s, 9H). 401.2216; ¹³C NMR (126 MHz, DMSO) d 163.24, 157.08, 156.91, found, 154.68, 147.50, 144.55, 137.06, 137.03, 136.61, 136.37, 401.2221 133.92, 131.88, 124.39, 122.36, 79.44, 35.28, 28.34, 26.26, 20.04, 15.64. 240 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.80-8.73 m/z 417.6 (m, 1H), 8.67 (s, 1H), 7.85 (dd, J = 8.4, 2.4 Hz, 1H), [M + H]⁺ 7.80-7.73 (m, 1H), 7.65-7.56 (m, 4H), 5.73 (s, 1H), 3.81 (s, 3H), 1.78 (s, 6H), 1.17 (s, 9H). IR (ATR) 2959, 1558, 1471, 1011 cm⁻¹. 241 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.83 (s, 2H), m/z 376.42 8.74 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 2.4, 8.3 Hz, 1H), 7.69 [M + H]⁺ (d, J = 8.3 Hz, 1H), 7.60-7.54 (m, 2H), 7.32 (d, J = 8.3 Hz, 2H), 3.33 (s, 3H), 2.04 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.96, 157.29, 155.22, 149.27, 147.23, 138.58, 136.10, 135.24, 134.07, 128.51, 124.27, 121.53, 120.51, 79.99, 51.029, 23.32. 242 ESIMS ¹H NMR (300 MHz, CDCl₃) δ = 9.13 (s, 1H), 8.98 (s, 2H), m/z 414.47 8.79-8.67 (m, 1H), 7.98-7.83 (m, 2H), 7.61-7.51 (m, [M + H]⁺ 2H), 7.32 (br d, J = 8.4 Hz, 2H), 3.79-3.65 (m, 1H), 3.63- 3.47 (m, 1H), 2.06 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 159.76, 157.87, 155.88, 147.81, 136.27, 135.97, 135.32, 128.57, 121.54, 120.47, 109.97, 87.62, 78.33, 60.81, 15.26, 3.95. 243 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.12 (s, 1H), 8.85 (s, 2H), m/z 400.4 8.74 (d, J = 1.8 Hz, 1H), 7.90-7.85 (m, 1H), 7.78-7.72 [M + H]⁺ (m, 1H), 7.60-7.55 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 4.16 (t, J = 2.4 Hz, 2H), 2.45 (t, J = 2.4 Hz, 1H), 2.11 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 161.17, 149.34, 147.27, 138.24, 135.94, 135.44, 134.38, 128.55, 122.14, 121.56, 120.74, 118.73, 109.97, 80.98, 79.84, 74.46, 52.26, 20.62. 244 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.08 (s, 1H), 8.82 (s, 2H), m/z 404.37 8.74-8.69 (m, 1H), 7.83 (dd, J = 2.4, 8.3 Hz, 1H), 7.71 (d, [M + H]⁺ J = 8.1 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.32 (br d, J = 8.1 Hz, 2H), 3.36 (q, J = 7.0 Hz, 2H), 2.68 (qd, J = 7.3, 14.7 Hz, 1H), 2.50 (qd, J = 7.2, 14.6 Hz, 1H), 1.32 (t, J = 7.0 Hz, 3H), 0.77 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 161.81, 157.15, 155.51, 149.24, 147.21, 137.76, 136.18, 134.97, 133.77, 128.50, 121.53, 121.27, 81.90, 57.84, 26.93, 15.39, 6.89. 246 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.19 (s, 1H) 8.76 (d, J = m/z 414 2.0 Hz, 1H ), 8.66 (s, 1H), 7.88-7.83 (m, 1H), 7.77 (d. [M + H]⁺ J = 8.4 Hz, 1H), 7.68-7.59 (m, 4H), 5.72 (bs, 1H), 3.82 (s, 3H), 1.96 (—F2CH3, t, J = 18,36.3 Hz, 3H), 1.16 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 166.42, 161.94, 157.51, 156.60, 145.10, 138.86, 138.27, 137.92, 133.96, 133.84, 127.11, 125.44, 125.37, 124.11, 123.04, 121.66, 80.34, 53.51, 40.32, 26.13. ¹⁹F NMR (282 MHz, CDCl₃) δ −87.59 (dd). 247 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H) 8.72 (d, J = m/z 384 2.4 Hz, 1H ), 8.66 (s, 1H), 7.83-7.73 (m, 2H), 7.52 (d. [M + H]⁺ J = 8.4 Hz, 2H), 7.45 (d. J = 8.4 Hz, 2H), 5.71 (s, 1H), 3.82 (s, 3H), 1.16 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 171.04, 166.35, 161.75, 157.51, 156.55, 144.84, 135.79, 134.30, 133.67, 133.50, 129.24, 128.18, 124.05, 122.99, 80.28, 60.31, 53.43, 40.28, 26.70. 248 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.16 (s, 1H), 9.01 (s, 2H), m/z 442.42 8.68 (s, 1H), 7.94 (q, J = 8.3 Hz, 2H), 7.44 (t, J = 8.4 Hz, [M + H]⁺ 1H), 7.17-7.03 (m, 2H), 4.47-4.38 (m, 1H), 4.35-4.24 (m, 1H), 2.44-2.32 (m, 1H), 2.08 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 160.99, 159.12, 158.42, 158.12, 156.02, 149.79, 149.68, 149.66, 149.11, 149.02, 137.34, 135.31, 131.16, 131.12, 129.94, 123.80, 121.57, 120.41, 118.99, 117.08, 109.80, 89.34, 79.02, 75.27, 74.73, 53.73. ¹⁹F NMR (282 MHz, CDCl₃): δ −57.97, −113.23. 249 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.15 (s, 1H), 8.86 (s, 2H), m/z 422.46 8.76 (s, 1H), 7.95-7.85 (m, 1H), 7.63-7.45 (m, 2H), [M + H]⁺ 7.15 (br t, J = 10.6 Hz, 2H), 3.06 (m, 4H), 0.88 (t, J = 6.6 Hz, 6H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.96 −113.17. 250 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.87 (s, 2H), m/z 444.43 8.67 (s, 1H), 7.94-7.88 (m, 1H), 7.86-7.81 (m, 1H), [M + H]⁺ 7.47 (t, J = 8.6 Hz, 1H), 7.20-7.06 (m, 2H), 4.23 (d, J = 2.0 Hz, 2H), 2.39 (t, J = 2.4 Hz, 1H), 1.72 (tt, J = 5.4, 8.3 Hz, 1H), 0.76 (d, J = 8.3 Hz, 2H), 0.62-0.53 (m, 1H), 0.44-0.36 (m, 1H). ¹⁹F NMR (376 MHz, CDCl₃) δ −57.95 −113.28. 251 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), m/z 417.6 8.74 (s, 1H), 8.01-7.94 (m, 1H), 7.87 (dd, J = 8.4, 0.9 [M + H]⁺ Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 8.5, 1.9 Hz, 1H), 6.16 (s, 1H), 2.94-2.83 (m, 2H), 2.65 (dt, J = 9.5, 5.9 Hz, 2H), 2.57-2.40 (m, 1H), 2.21-2.06 (m, 1H), 1.09 (s, 9H). 252 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.25 (s, 2H), 9.10 (s, 1H), m/z 415.6 8.37 (d, J = 1.4 Hz, 1H), 7.91-7.84 (m, 1H), 7.60 (dd, J = [M + H]⁺ 8.2, 2.2 Hz, 1H), 7.23 (d, J = 9.2 Hz, 2H), 6.35 (s, 1H), 2.04 (d, J = 18.9 Hz, 6H), 1.76 (s, 6H), 1.08 (s, 9H). 253 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.68 (s, 2H), 9.13 (s, 1H), m/z 433.6 8.84 (d, J = 1.9 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.89 [M + H]⁺ (ddd, J = 8.8, 6.5, 2.6 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 4.83 (q, J = 8.5 Hz, 2H), 3.19 (s, 3H), 0.90 (s, 9H). ¹⁹F NMR (376 MHz, CDCl₃) δ −73.79 (s). 254 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.67 (s, 1H), m/z 429.6 8.46 (dd, J = 2.3, 0.8 Hz, 1H), 7.73 (dd, J = 8.3, 0.8 Hz, [M + H]⁺ 1H), 7.58 (dd, J = 8.3, 2.3 Hz, 1H), 7.26-7.12 (m, 3H), 5.73 (s, 1H), 3.81 (s, 3H), 2.27 (s, 3H), 1.76 (q, J = 5.0 Hz, 2H), 1.45 (q, J = 5.3 Hz, 2H), 1.18 (s, 9H). IR (ATR) 2958, 2237, 1559, 1470 cm⁻¹. 255 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.86 (s, 2H), m/z 426.42 8.76-8.70 (m, 1H), 7.92-7.87 (m, 1H), 7.86-7.78 (m, [M + H]⁺ 1H), 7.64-7.53 (m, 2H), 7.33 (d, J = 7.8 Hz, 2H), 4.22 (d, J = 2.2 Hz, 2H), 2.39 (t, J = 2.4 Hz, 1H), 1.72 (tt, J = 5.5, 8.3 Hz, 1H), 0.76 (d, J = 8.4 Hz, 2H), 0.63-0.51 (m, 1H), 0.44-0.34 (m, 1H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.8. 256 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.70 (s, 1H), m/z 435.6 8.67 (s, 1H), 7.87-7.81 (m, 1H), 7.77 (dd, J = 8.4, 0.8 [M + H]⁺ Hz, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.2, 2.0 Hz, 1H), 7.31 (dd, J = 11.7, 1.9 Hz, 1H), 5.72 (s, 1H), 3.82 (s, 3H), 1.77 (s, 6H), 1.17 (s, 9H). IR (ATR) 2959, 2361, 1471, 1011 cm⁻¹. 257 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.69 (s, 2H), 9.13 (s, 1H), m/z 432.6 8.88-8.82 (m, 1H), 7.89 (dd, J = 8.4, 2.5 Hz, 1H), 7.64 [M + H]⁺ (dd, J = 8.4, 0.8 Hz, 1H), 7.62-7.56 (m, 2H), 7.08 (d, J = 8.8 Hz, 2H), 4.42 (q, J = 8.1 Hz, 2H), 3.19 (s, 3H), 0.89 (s, 9H). IR (ATR) 2959, 1476, 1239, 1163 cm⁻¹. 258 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.94 (s, 2H), m/z 376.35 8.74 (d, J = 1.5 Hz, 1H), 7.89 (dd, J = 2.4, 8.4 Hz, 1H), [M + H]⁺ 7.61-7.53 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 5.77 (s, 1H), 2.43-2.30 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃): δ 160.61, 157.35, 155.036, 149.50, 146.14, 139.26, 135.98, 135.61, 134.64, 128.59, 121.75, 121.61, 120.06, 75.56, 33.80, 7.64. 259 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 1H), 9.05 (s, 2H), m/z 459.4 8.84-8.78 (m, 1H), 7.87 (dd, J = 8.4, 2.5 Hz, 1H), 7.68- [M + H]⁺ 7.55 (m, 5H), 1.78 (s, 6H), 1.10 (s, 9H), 0.00 (s, 9H). IR (ATR) 2959, 1412, 1252, 1096 cm⁻¹. 260 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.11 (s, 1H), 8.84 (s, 2H), m/z 414.4 8.74 (d, J = 1.5 Hz, 1H), 7.90-7.82 (m, 1H), 7.77-7.71 [M + H]⁺ (m, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.33 (br d, J = 8.4 Hz, 2H), 4.05 (d, J = 2.2 Hz, 2H), 2.76-2.61 (m, 1H), 2.60- 2.47 (m, 1H), 2.47-2.42 (m, 1H), 0.83 (t, J = 7.3 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 160.53, 157.40, 155.52, 149.34, 147.32, 136.82, 135.97, 135.19, 131.17, 128.52, 121.53, 83.34, 79.46, 74.37, 51.65, 27.17, 7.08. 261 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.70 (s, 2H), 9.13 (s, 1H), m/z 432.5 8.61 (d, J = 1.1 Hz, 1H), 7.75-7.63 (m, 3H), 7.19-7.12 [M + H]⁺ (m, 2H), 3.21 (s, 3H), 2.31 (s, 3H), 0.90 (s, 9H). IR (ATR) 2961, 2360, 1411, 1211 cm⁻¹. 262 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 8.85 (t, J = 1.8 Hz, 1H), m/z 404.5 8.76 (d, J = 1.5 Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H), 8.01- [M + H]⁺ 7.92 (m, 2H), 7.89 (dd, J = 8.3, 0.7 Hz, 1H), 7.61 (s, 4H), 6.33 (s, 1H), 1.78 (s, 6H), 1.09 (s, 9H). ¹⁹F NMR (376 MHz, CDCl₃) δ −127.55 (s). 263 HRMS-ESI ¹H NMR (400 MHz, DMSO-d6) d 9.43 (s, 2H), 9.06 (s, (m/z) 1H), 8.76 (dd, J = 2.3, 0.7 Hz, 1H), 7.97 (dd, J = 8.4, 2.3 [M + H]+ Hz, 1H), 7.88 (dd, J = 8.4, 0.9 Hz, 1H), 7.52-7.41 (m, calcd for 1H), 7.22 (d, J = 6.9 Hz, 2H), 6.22 (s, 1H), 3.85 (s, 3H), C₂₅H₂₈N₄O₂, 1.76 (s, 6H), 0.95 (s, 9H). 416.2212; ¹³C NMR (126 MHz, DMSO) d 161.07, 155.98, 155.80, found, 146.29, 142.57, 136.10, 130.68, 130.17, 124.87, 123.94, 416.2204 121.33, 117.09, 108.17, 78.32, 55.19, 36.29, 27.64, 25.24. 264 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.24 (s, 2H), 9.09 (s, 1H), m/z 429.4 8.59-8.51 (m, 1H), 7.85 (dd, J = 8.2, 0.7 Hz, 1H), 7.76 [M + H]⁺ (dd, J = 8.3, 2.2 Hz, 1H), 7.34-7.27 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 2.30 (s, 3H), 2.08 (dd, J = 13.9, 7.3 Hz, 2H), 1.95 (dd, J = 13.9, 7.3 Hz, 2H), 1.09 (s, 9H), 0.96 (t, J = 7.4 Hz, 6H). IR (ATR) 2970, 2234, 1409, 908 cm⁻¹. 265 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 2H), 9.09 (s, 1H), m/z 421.5 8.63 (dd, J = 2.1, 0.9 Hz, 1H), 7.95-7.82 (m, 2H), 7.62 [M + H]⁺ (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.0, 2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.16 (s, 1H), 1.78 (s, 6H), 1.10 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 159.58, 156.93, 156.42, 147.20, 143.49, 137.54, 137.02, 135.60, 133.54, 133.40, 131.67, 127.10, 124.25, 123.64, 121.53, 40.15, 36.90, 28.98, 26.34. 266 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 9.01 (s, 2H), m/z 386.42 8.74 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 2.0, 8.3 Hz, 1H), [M + H]⁺ 7.60-7.54 (m, 3H), 7.37-7.31 (m, 2H), 6.06 (bs, 1H), 2.01 (s, 3H). ¹³C NMR (101 MHz, CDCl₃): δ 158.79, 157.97, 155.29, 149.54, 145.90, 137.83, 136.38, 135.46, 135.42, 128.65, 121.63, 121.20, 85.22, 79.17, 70.67, 3.85. 267 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.70 (s, 2H), 9.13 (s, 1H), m/z 415.6 8.65-8.59 (m, 1H), 7.70 (dd, J = 8.3, 2.3 Hz, 1H), 7.65 [M + H]⁺ (d, J = 8.3 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.0, 1.9 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 3.22 (s, 3H), 2.33 (s, 3H), 1.78 (s, 6H), 0.91 (s, 9H). IR (ATR) 2978, 2234, 1410, 1069 cm⁻¹. 268 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 2H), 9.09 (s, 1H), m/z 433.6 8.76 (d, J = 0.9 Hz, 1H), 8.05-7.94 (m, 1H), 7.87 (dd, J = [M + H]⁺ 8.5, 0.8 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.33 (dd, J = 8.1, 2.0 Hz, 1H), 7.27-7.19 (m, 1H), 6.19 (s, 1H), 2.21- 2.03 (m, 2H), 1.94 (dd, J = 14.0, 7.3 Hz, 2H), 1.09 (s, 9H), 0.97 (t, J = 7.4 Hz, 6H). IR (ATR) 2971, 2235, 1411, 909 cm⁻¹. 269 ESIMS ¹H NMR (400 MHz, CDCl₃) δ = 9.08 (s, 1H), 8.82 (s, m/z 408.35 2H), 8.67 (s, 1H), 7.84 (td, J = 1.8, 8.2 Hz, 1H), 7.73 (d, [M + H]⁺ J = 8.3 Hz, 1H), 7.45 (t, J = 8.3 Hz, 1H), 7.12 (dd, J = 10.0, 14.9 Hz, 2H), 3.26 (s, 3H), 2.71-2.64 (m, 1H), 2.53-2.43 (s, 1H), 0.78 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.75, 160.97, 158.47, 157.21, 155.59, 149.61, 149.50, 148.61, 148.18, 137.27, 136.83, 136.80, 128.94, 128.92, 124.09, 121.57, 121.04, 119.01, 117.06, 117.03, 109.77, 109.51, 82.32, 50.44, 26.35. ¹⁹F NMR (376 MHz, CDCl₃) δ −57.98, −113.30. 270 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 9.00 (s, 2H), m/z 424.4 8.74 (d, J = 1.5 Hz, 1H), 7.96-7.87 (m, 2H), 7.59-7.48 [M + H]⁺ (m, 2H), 7.32 (d, J = 8.3 Hz, 2H), 4.44-4.38 (m, 1H), 4.33-4.25 (m, 1H), 2.41 (t, J = 2.4 Hz, 1H), 2.08 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 158.77, 158.10, 155.99, 149.42, 147.85, 135.83, 135.41, 128.59, 121.57, 120.65, 89.27, 79.27, 75.34, 74.71, 74.67, 53.71, 4.02. 271 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.47 (s, 1H), 8.69 (s, 1H), m/z 422.2 8.52-8.47 (m, 2H), 8.36 (d, J = 8.4 Hz, 1H), 7.85 (d, J = [M + H]⁺ 8.7 Hz, 1H), 7.50-7.44 (m, 1H), 7.15-7.08 (m, 2H), 6.73 (s, 1H), 1.01 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 161.41, 159.58, 157.94, 145.84, 142.51, 141.10, 136.00, 131.18, 129.07, 124.01, 123.83, 117.07, 109.84, 109.49, 80.18, 41.04, 26.03. 272 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.83 (s, 2H), m/z 418.43 8.80 (d, J = 2.2 Hz, 1H), 7.90 (dd, J = 2.4, 8.3 Hz, 1H), [M + H]⁺ 7.66-7.53 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 3.23-2.99 (m, 3H), 1.17 (t, J = 7.0 Hz, 3H), 0.88 (dd, J = 7.0, 8.4 Hz, 6H). ¹⁹F NMR (282.2 MHz, CDCl₃) δ −57.8. 273 ESIMS ¹H NMR (300 MHz, CDCl₃) δ 9.19 (s, 1H), 8.72 (d, J = m/z 415 2.4 Hz, 1H), 8.66 (s, 1H), 7.84-7.73 (m, 2H), 7.06 (s, [M + H]⁺ 1H), 7.57 (d. J = 7.8 Hz, 1H), 7.25 (d. J = 2.7 Hz, 1H), 7.22 (s, 1H), 6.56 (t, J = 147.3 Hz, 1H), 3.82 (s, 3H), 1.16 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 166.45, 161.58, 157.45, 156.55, 144.91, 134.69, 133.75, 133.65, 128.43, 124.15, 123.01, 120.19, 115.73, 112.27, 80.32, 53.49, 40.31, 26.75. ¹⁹F NMR (282 MHz, CDCl₃) δ −80.98 (d) 274 ESIMS ¹H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 2H), 9.07 (s, m/z 419 1H), 8.62 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 8.4, 0.8 Hz, [M + H]⁺ 1H), 7.85 (dd, J = 8.3, 2.3 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 10.6, 1.8 Hz, 1H), 6.28 (s, 1H), 2.19 (s, 3H), 1.74 (s, 6H), 0.94 (s, 9H). ¹³C NMR (126 MHz, DMSO-d6) δ 162.05, 159.89, 159.16-156.54 (m), 155.94 (d, J = 21.5 Hz), 146.78, 142.66 (d, J = 8.3 Hz), 142.05 (d, J = 7.7 Hz), 140.16- 134.58 (m), 127.08, 124.22-121.42 (m), 110.52 (d, J = 24.7 Hz), 109.82-108.93 (m), 35.87 (dd, J = 17.1, 1.9 Hz), 27.36 (d, J = 13.9 Hz), 25.16, 21.69 (d, J = 2.8 Hz), 19.36 (d, J = 3.0 Hz). 275 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 2H), 9.08 (s, 1H), m/z 435.3 8.75 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 8.3, 2.3 Hz, 1H), [M + H]⁺ 7.81 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 6.36 (s, 1H), 2.54 (s, 2H), 2.41 (s, 6H), 1.35 (s, 6H), 1.08 (s, 9H). IR (ATR) 2970, 1472, 1408, 119 cm⁻¹. 276 ESIMS ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 2H), 9.08 (s, 1H), m/z 449.4 8.73 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 8.3, 2.3 Hz, 1H), [M + H]⁺ 7.80 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.34 (s, 1H), 3.18 (s, 3H), 2.98 (s, 3H), 1.68 (s, 6H), 1.07 (s, 9H). IR (ATR) 2955, 1624, 1408, 1154 cm⁻¹. 277 ESIMS ¹H NMR (400 MHz, CDCl₃) d 9.69 (s, 2H), 9.13 (s, 1H), m/z 418 8.87 (d, J = 1.9 Hz, 1H), 7.91 (dd, J = 8.4, 2.5 Hz, 1H), [M + H]⁺ 7.66 (ddd, J = 9.5, 6.9, 1.7 Hz, 3H), 7.35 (d, J = 8.0 Hz, 2H), 3.20 (s, 3H), 0.90 (s, 9H). ¹⁹F NMR (376 MHz, CDCl₃) d −57.80 (s, 3F). 278 ESIMS ¹H NMR (400 MHz, CDCl₃) d 9.23 (s, 2H), 9.08 (s, 1H), m/z 412.2 8.80 (dd, J = 2.2, 0.8 Hz, 1H), 8.00-7.94 (m, 2H), 7.91 [M + H]⁺ (d, J = 8.3 Hz, 2H), 7.84 (dd, J = 8.3, 2.1 Hz, 1H), 5.84 (s, 1H), 2.02 (s, 6H), 1.09 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) d 161.02, 156.98, 156.39, 145.35, 143.28, 137.59, 136.80, 134.98, 134.13, 132.58, 131.71, 128.27, 122.58, 122.49, 117.50, 111.13, 79.67, 40.19, 37.88, 27.47, 26.28. 279 ESIMS ¹H NMR (400 MHz, CDCl₃) d 9.22 (s, 2H), 9.08 (s, 1H), m/z 399.2 8.78 (d, J = 1.6 Hz, 1H), 7.96 (dd, J = 8.4, 2.4 Hz, 1H), [M + H]⁺ 7.86 (d, J = 8.4 Hz, 1H), 7.67-7.60 (m, 2H), 7.60-7.52 (m, 2H), 6.21 (s, 1H), 2.95-2.81 (m, 2H), 2.75-2.58 (m, 2H), 2.49 (ddd, J = 17.6, 11.5, 8.7 Hz, 1H), 2.25-2.06 (m, 1H), 1.09 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) d 159.39, 156.88, 156.40, 145.40, 140.12, 137.13, 136.45, 135.04, 135.01, 127.64, 126.52, 124.06, 122.20, 79.47, 40.12, 39.99, 34.71, 26.33, 17.10.

TABLE 3 Rating Scale For Disease Control in Wheat Leaf Bloth Assay (SEPTTR). % Disease Control Rating  80-100 A 60-79 B 40-59 C <40 D Not tested E

TABLE 4 Biological Activity - Disease Control in High and Low Volume Assays. SI SEPTTR SI SEPTTR FI SEPTTR Type A Assay Type B Assay Type B Assay Compound (50 ppm) (100 g/ha) (100 g/ha) Number 1 DP 3 DC 3 DC 3 DP 3 DC 3 DP 1 D C E E E E 2 A D E E E E 3 D A A A B C 4 B D E E E E 5 D C E E E E 6 A A E E E E 7 A A E E E E 8 A A E E E E 9 A A E E E E 10 A A E E E E 11 C C E E E E 12 A D E E E E 13 A A B A C B 14 A A B B C B 15 B C E E E E 16 A A E E E E 17 A A A A B B 18 D D E E E E 19 D C E E E E 20 E E E E E E 21 A A E E E E 22 A A E E E E 23 D B E E E E 24 D D E E E E 25 C A E E E E 26 D C E E E E 27 A A A A A A 28 B C E E E E 29 A A E E E E 30 E E E E E E 31 D B E E E E 32 A A E E E E 33 A B E E E E 34 A B E E E E 35 D B E E E E 36 D B E E E E 37 E E E E E E 38 A A A A A C 39 A A A A B C 40 A B E E E E 41 A A A A D B 42 A A E E E E 43 B A E E E E 44 D D E E E E 45 E E E E E E 46 A A E E E E 47 C A E E E E 48 D D E E E E 49 B A E E E E 50 D B E E E E 51 A A C B B B 52 B B E E E E 53 C D E E E E 54 D C E E E E 55 D D E E E E 56 A A E E E E 57 A A A A D D 58 B A E E E E 59 A A A A A A 60 A A A A D B 61 C B E E E E 62 C C E E E E 63 A A A A C B 64 A A A A B A 65 A E A A B B 66 A E E E E E 67 D E E E E E 68 A E E E E E 69 A E E E E E 70 C E E E E E 71 E E E E E E 72 D E E E E E 73 A E A A B B 74 A E A A C D 75 A E E E E E 76 A E E E E E 77 A E E E E E 78 A E A A B B 79 A E E E E E 80 A E A A A A 81 A E A B D A 82 A E A A A A 83 C E D C A C 84 A E A A B B 85 A E E E E E 86 B E A A A A 87 A E E E E E 88 A E A A A A 89 A E A A C B 90 A E A A A A 91 A E B A C A 92 A E A A A A 93 A E A A B A 94 B E E E E E 95 A E A A A A 96 A E A A A A 97 A E A A A A 98 A E A A A A 99 A E E E D C 100 A E E E E E 101 A E A A A A 102 A E A A A A 103 A E B A D A 104 A E A A D A 105 A E A A A A 106 A E A A A A 107 A E A B A B 108 B E E E E E 109 B E E E E E 110 A E E E E E 111 B E E E E E 112 A E A A A A 113 B E E E E E 114 B E A A A B 115 A E A A A A 116 B E A A A B 117 A E A A A A 118 A E A A A A 119 A E A A B C 120 A E A A A B 121 A E A A A B 122 A E A A B B 123 B E E E E E 124 A E A A A A 125 A E A A A B 126 B E E E E E 127 A E E E E E 128 A E E E E E 129 B E E E E E 130 A E A A A A 131 A E A B B B 132 E E E E A A 133 E E E E E E 134 E E E E E E 135 E E E E E E 136 A E E E E E 137 A E E E E E 138 A E E E E E 139 A E E E E E 140 A E E E E E 141 B E E E E E 142 A E E E E E 143 A E A B A A 144 A E E E E E 145 A E A B A A 146 A E A A A B 147 A E E E E E 148 E E B D B D 149 E E A B A B 150 A E E E A A 151 A E A A E E 152 A E A A A A 153 A E E E E E 154 A E E E E E 155 A E E E B B 156 A E A A A A 157 A E A A A A 158 A E A A A A 159 A E E E E E 160 A E E E A A 161 A E E E A A 162 A E E E A A 163 A E E E A A 164 E E E E A A 165 E E E E A A 166 E E E E A A 167 A E A B A A 168 B E E E E E 169 A E A B A A 170 A E E E E E 171 A E E E E E 172 A E E E E E 173 E E E E A A 174 E E E E B A 175 E E E E A A 176 E E E E D B 177 E E E E D B 178 E E E E D B 179 E E E E A A 180 E E E E B C 181 E E E E D B 182 E E E E D B 183 E E E E A A 184 E E E E D C 185 E E E E D A 186 E E E E C A 187 E E E E A A 188 E E E E B A 189 E E E E C A 190 E E E E B C 191 E E E E D A 192 E E E E A A 193 E E E E D B 194 E E E E D A 195 E E E E D C 196 E E E E E E 197 E E E E D A 198 E E E E D A 199 E E E E C A 200 E E E E D A 201 E E E E B A 202 E E E E B B 203 E E E E C A 204 E E E E D B 205 E E E E C A 206 E E E E D C 207 E E E E C B 208 E E E E D A 210 E E E E A A 211 E E E E A A 212 E E E E A A 213 E E E E B B 214 E E E E D A 215 E E E E D D 216 E E E E A A 217 E E E E D D 218 E E E E D A 219 E E E E C B 220 E E E E D A 221 E E E E D C 222 E E E E C B 223 E E E E A A 224 E E E E C B 225 E E E E A B 226 E E E E A A 227 E E E E D C 228 E E E E A A 229 E E E E B B 230 E E E E D A 231 E E E E D B 232 E E E E D B 233 E E E E A A 234 E E E E C B 235 E E E E B A 236 E E E E A A 237 E E E E D C 238 E E E E B D 239 E E E E A A 240 E E E E A A 241 E E E E D C 242 E E E E D C 243 E E E E D A 244 E E E E D C 246 E E E E B A 247 E E E E D A 248 E E E E D C 249 E E E E B A 250 E E E E D A 251 E E E E A A 252 E E E E A A 253 E E E E A A 254 E E E E E E 255 E E E E D B 256 E E E E A A 257 E E E E B B 258 E E E E D B 259 E E E E B A 260 E E E E D C 261 E E E E A A 262 E E E E A A 263 E E E E A A 264 E E E E A A 265 E E E E A A 266 E E E E D B 267 E E E E B A 268 E E E E A A 269 E E E E C A 270 E E E E D C 271 E E E E D A 272 E E E E D B 273 E E E E D A 274 E E E E E E 275 E E E E E E 276 E E E E E E 277 E E A A A A 278 E E E E E E 279 E E E E E E * SI - SEPTTR standard laboratory isolate * FI - SEPTTR field isolate *SEPTTR - Wheat Leaf Blotch (Septoria tritici) *ppm - Parts per million *g/ha - Grams per hectare *1 DP - 1 Day Protectant *3 DC - 3 Day Curative *3 DP - 3 Day Protectant 

What is claimed is:
 1. A compound of Formula I, or salt thereof, wherein:

Z is optionally substituted 5-pyrimidinyl, optionally substituted 4-pyrimidinyl, optionally substituted oxazolyl, optionally substituted 3-pyridinyl, optionally substituted 4-pyridinyl, or tetrazolyl; n is 0 or 1; R₁ is alkyl, alkynyl, haloalkyl, aryl, or heteroaryl, each optionally substituted with 0, 1, 2 or 3 independent R₄; R₂ is aryl, heteroaryl aryloxy, heteroaryloxy, arylalkynyl, heteroarylalkynyl, arylalkyl, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, aryloxyalkyl, or heteroaryloxyalkyl wherein each aryl or heteroaryl is optionally substituted with 0, 1, 2 or 3 independent R₄; R₃ is independently H, alkyl, aryl, substituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl, —C(O)alkyl, —C(O)aryl, —Si(alkyl)₃, each optionally substituted with 0, 1, 2 or 3 independent R₄; R₄ is independently aryl, heteroaryl, alkyl, thioalkyl, cyano, haloalkyl, cyanoalkyl, hydroxy, alkoxy, halo, haloalkoxy, —C(O)alkyl, —C(O)OH, —C(O)Oalkyl, —SCF₃, —SF₅, —SCN, or SO₂(alkyl), —Si(alkyl)₃, or oxime; and R₅-R₇ are independently selected from the group consisting of H, alkyl, alkoxy, halo, and haloalkyl.
 2. The compound of claim 1, wherein R₁ is alkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, alkynyl, or heteroarylalkyl.
 3. The compound of claim 1, wherein R₂ is phenyl, 2-pyridinyl, 3-pyridinyl, or 5-pyrimidinyl optionally substituted with 1, 2 or 3 independent R₄.
 4. The compound of claim 3, wherein R₄ is halo, haloalkyl, haloaryl, cyanoalkyl, haloalkoxy, or cyano.
 5. The compound of claim 3, wherein R₂ is phenyl substituted at the 4 position with a halo, haloalkyl, cyanoalkyl, haloalkoxy, or cyano substituent.
 6. The compound of claim 3, wherein R₂ is 2-pyridinyl substituted at the 5 position with a halo, haloalkyl, cyanoalkyl, haloalkoxy, or cyano substituent.
 7. The compound of claim 3, wherein R₂ is 3-pyridinyl substituted at the 6 position with a halo, haloalkyl, cyanoalkyl, haloalkoxy, or cyano substituent.
 8. The compound of claim 1, wherein R₂ is aryloxy or heteroaryloxy optionally substituted with 1, 2 or 3 independent R₄.
 9. The compound of claim 8, wherein R₁ is alkyl, haloalkyl, cycloalkyl, aryl, or heteroarylaryl optionally substituted with 1, 2 or 3 independent R₄.
 10. The compound of claim 9, wherein R₁ is methyl, ethyl, tert-butyl, iso-propyl, cyclopropyl, trifluoromethyl, 2,4-difluorophenyl, 2-fluoro-4-chlorophenyl, —CF₂-(2,4-difluorophenyl), —CF₂-(2-fluoro-4-chlorophenyl), —CH₂-(2,4-difluorophenyl), or —CH₂-(2-fluoro-4-chlorophenyl).
 11. The compound of claim 8, wherein R₂ is phenoxy, (2-pyridinyl)oxy, (3-pyridinyl)oxy, or (5-pyrimidinyl)oxy optionally substituted with 1, 2 or 3 independent R₄.
 12. The compound of claim 11, wherein R₄ is halo, haloalkyl, cyanoalkyl, haloalkoxy, or cyano.
 13. A method of treating a metalloenzyme-mediated disease or disorder in or on a plant comprising contacting a compound of claim 1 with the plant or seeds.
 14. A method of treating or preventing a fungal disease or disorder in or on a plant comprising contacting a compound of claim 1 with the plant or seeds.
 15. A method of treating or preventing fungal growth in or on a plant comprising contacting a compound of claim 1 with the plant or seeds.
 16. A method of inhibiting microorganisms in or on a plant comprising contacting a compound of claim 1 with the plant or seeds.
 17. A composition comprising a compound of claim 1 and an agriculturally acceptable carrier.
 18. A composition for the control of a fungal pathogen including mixtures of at least one of the compounds of claim 1 with other pesticides including fungicides, insecticides, nematocides, miticides, arthropodicides, bactericides and combinations thereof.
 19. The compositions according to claim 18, wherein the fungal pathogen is one of Leaf Blotch of Wheat (Mycosphaerella graminicola; anamorph: Septaria tritici), Wheat Brown Rust (Puccinia triticina), Stripe Rust (Puccinia striiformis), Scab of Apple (Venturia inaequalis), Blister Smut of Maize (Ustilago maydis), Powdery Mildew of Grapevine (Uncinula necator), Barley Scald (Rhynchosporium secalis), Blast of Rice (Magnaporthe grisea), Rust of Soybean (Phakopsora pachyrhizi), Glume Blotch of Wheat (Leptosphaeria nodorum), Powdery Mildew of Wheat (Blumeria graminis f sp. tritici), Powdery Mildew of Barley (Blumeria graminis f sp. hordei), Powdery Mildew of Cucurbits (Erysiphe cichoracearum), Anthracnose of Cucurbits (Glomerella lagenarium), Leaf Spot of Beet (Cercospora beticola), Early Blight of Tomato (Alternaria solani), and Net Blotch of Barley (Pyrenophora teres).
 20. A method for the control and prevention of fungal attack on a plant, the method including the step of: Applying a fungicidally effective amount of at least one of the compounds of claim 1 to at least one of the plant, an area adjacent to the plant, soil adapted to support growth of the plant, a root of the plant, a seed of the plant, and foliage of the plant. 